8-(Biaryl)quinoline pde4 inhibitors

ABSTRACT

8-(biaryl) quinolines wherein the bi-aryl group at the 8-position is in a meta relationship to the quinoline group, are PDE4 inhibitors useful in the treatment of asthma, chronic bronchitis, chronic obstructive pulmonary disease, eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock, laminitis in horses, colic in horses, septic shock, ulcerative colitis, Crohn&#39;s disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, ortherosclerosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection, graft versus host disease, hypersecretion of gastric acid, bacterial, fungal induced sepsis, viral induced sepsis, fungal induced septic shock, viral induced septic shock, inflammation-mediated chronic tissue degeneration, cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, tumour growth, or cancerous invasion of normal tissues. In another aspect, the present invention is directed to a method of enhancing cognition in a healthy subject comprising administering a safe cognition enhancing amount of phosphodiesterase-4 inhibitor. In particular, this invention is directed to a method of enhancing memory, learning, retention, recall, awareness and judgement in health subjects comprising administering a safe and cognition enhancing amount of a phosphodiesterase-4 inhibitor.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to compounds that are substituted8-(biaryl)quinolines. In particular, this invention is directed tosubstituted 8-(biaryl)quinolines which are phosphodiesterase-4inhibitors wherein the biaryl group at the 8-position is in a metarelationship to the quinoline group.

2. Related Background

Hormones are compounds that variously affect cellular activity. In manyrespects, hormones act as messengers to trigger specific cellularresponses and activities. Many effects produced by hormones, however,are not caused by the singular effect of just the hormone. Instead, thehormone first binds to a receptor, thereby triggering the release of asecond compound that goes on to affect the cellular activity. In thisscenario, the hormone is known as the first messenger while the secondcompound is called the second messenger. Cyclic adenosine monophosphate(adenosine 3′,5′-cyclic monophosphate, “cAMP” or “cyclic AMP”) is knownas a second messenger for hormones including epinephrine, glucagon,calcitonin, corticotrophin, lipotropin, luteinizing hormone,norepinephrine, parathyroid hormone, thyroid-stimulating hormone, andvasopressin. Thus, cAMP mediates cellular responses to hormones. CyclicAMP also mediates cellular responses to various neurotransmitters.

Phosphodiesterases (“PDE”) are a family of enzymes that metabolize 3′,5′ cyclic nucleotides to 5′ nucleoside monophosphates, therebyterminating cAMP second messenger activity. A particularphosphodiesterase, phosphodiesterase-4 (“PDE4”, also known as “PDE-IV”),which is a high affinity, cAMP specific, type IV PDE, has generatedinterest as potential targets for the development of novelanti-asthmatic and anti-inflammatory compounds. PDE4 is known to existas at lease four isoenzymes, each of which is encoded by a distinctgene. Each of the four known PDE4 gene products is believed to playvarying roles in allergic and/or inflammatory responses. Thus, it isbelieved that inhibition of PDE4, particularly the specific PDE4isoforms that produce detrimental responses, can beneficially affectallergy and inflammation symptoms. It would be desirable to providenovel compounds and compositions that inhibit PDE4 activity.

A major concern with the use of PDE4 inhibitors is the side effect ofemesis which has been observed for several candidate compounds asdescribed in C. Burnouf et al., (“Burnouf”), Ann. Rep. In Med. Chem.,33:91-109(1998). B. Hughes et al., Br. J. Pharmacol.,118:1183-1191(1996); M. J. Perry et al., Cell Biochem. Biophys.,29:113-132(1998); S. B. Christensen et al., J. Med. Chem.,41:821-835(1998); and Burnouf describe the wide variation of theseverity of the undesirable side effects exhibited by various compounds.As described in M. D. Houslay et al., Adv. In Pharmacol.,44:225-342(1998) and D. Spina et al., Adv. In Pharmacol.,44:33-89(1998), there is great interest and research of therapeutic PDE4inhibitors.

International Patent Publication WO9422852 describes quinolines as PDE4inhibitors. International Patent Publication WO9907704 describes1-aryl-1,8-naphthylidin-4-one derivatives as PDE4 inhibitors.

A. H. Cook, et al., J. Chem. Soc., 413417(1943) describesgamma-pyridylquinolines. Other quinoline compounds are described in KeiManabe et al., J. Org. Chem., 58(24):6692-6700(1993); Kei Manabe et al.,J. Am. Chem. Soc., 115(12):5324-5325(1993); and Kei Manabe et al., J.Am. Chem. Soc., 114(17):6940-6941(1992).

Compounds that include ringed systems are described by variousinvestigators as effective for a variety of therapies and utilities. Forexample, International Patent Publication No. WO 98/25883 describesketobenzamides as calpain inhibitors, European Patent Publication No. EP811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541 describesubstituted benzoylguanidine sodium channel blockers, U.S. Pat. No.5,736,297 describes ring systems useful as a photosensitive composition.

U.S. Pat. Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958,5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593,5,891,896, and International Patent Publication WO 95/35283 describePDE4 inhibitors that are tri-substituted aryl or heteroaryl phenylderivatives. U.S. Pat. No. 5,580,888 describes PDE4 inhibitors that arestyryl derivatives. U.S. Pat. No. 5,550,137 describes PDE4 inhibitorsthat are phenylaminocarbonyl derivatives. U.S. Pat. No. 5,340,827describes PDE4 inhibitors that are phenylcarboxamide compounds. U.S.Pat. No. 5,780,478 describes PDE4 inhibitors that are tetra-substitutedphenyl derivatives. International Patent Publication WO 96t00215describes substituted oxime derivatives useful as PDE4 inhibitors. U.S.Pat. No. 5,633,257 describes PDE4 inhibitors that are cyclo(alkyl andalkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.

However, there remains a need for novel compounds and compositions thattherapeutically inhibit PDE4 with minimal side effects.

SUMMARY OF THE INVENTION

The present invention is directed to novel substituted8-(biaryl)quinolines that are PDE4 inhibitors, wherein the biaryl groupat the 8-position is in a meta relationship to the quinoline group. Thisinvention also provides a pharmaceutical composition which includes aneffective amount of the novel substituted 8-arylquinoline and apharmaceutically acceptable carrier.

This invention further provides a method of treatment in mammals of, forexample, i) Pulmonary disorders such as asthma, chronic bronchitis,chronic obstructive pulmonary disease (COPD), adult respiratory distresssyndrome, infant respiratory distress syndrome, cough, chronicobstructive pulmonary disease in animals, adult respiratory distresssyndrome, and infant respiratory distress syndrome, ii) Gastrointestinaldisorders such as ulcerative colitis, Crohn's disease, andhypersecretion of gastric acid, iii) Infectious diseases such asbacterial, fungal or viral induced sepsis or septic shock, endotoxicshock (and associated conditions such as laminitis and colic in horses),and septic shock, iv) Neurological disorders such as spinal cord trauma,head injury, neurogenic inflammation, pain, and reperfusion injury ofthe brain, v) Inflammatory disorders such as psoriatic arthritis,rheumatoid arritis, ankylosing spondylitis, osteoarthritis, inflammationand cytokine-mediated chronic tissue degeneration, vi) Allergicdisorders such as allergic rhinitis, allergic conjunctivitis, andeosinophilic granuloma, vii) Psychiatric disorders such as depression,memory impairment, and monopolar depression, viii) Neurodegenerativedisorders such as Parkinson disease, Alzheimer's disease, acute andchronic multiple sclerosis, ix) Dermatological disorders such aspsoriasis and other benign or malignant proliferative skin diseases,atopic dermatitis, and urticaria, x) Oncological diseases such ascancer, tumor growth and cancerous invasion of normal tissues, xi)Metabolic disorders such as diabetes insipidus, xii) Bone disorders suchas osteoporosis, and xiii) Cardiovascular disorders such as arterialrestenosis, atherosclerosis, reperfusion injury of the myocardium, andxiv) Other disorders such as chronic glomerulonephritis, vernalconjunctivitis, transplant rejection and graft versus host disease, andcachexia—maladies that are amenable to amelioration through inhibitionof the PDE4 isoenzyme and the resulting elevated cAMP levels—by by theadministration of an effective amount of the novel substituted8-(biaryl)quinoline or a precursor compound which forms in vivo thenovel substituted 8-(biaryl)quinoline.

In another aspect, the present invention is directed to a method ofenhancing cognition in a healthy subject comprising administering a safecognition enhancing amount of a phosphodiesterase-4 inhibitor. Inparticular, this invention is directed to a method of enhancing memory,learning, retention, recall, awareness and judgement in health subjectscomprising administering a safe and cognition enhancing amount of aphosphodiesterase-4 inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

A compound of this invention is represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

-   -   A is C or N;    -   X is phenyl, pyridyl, pyrazinyl, thiaphenyl, quinolinyl,        benzofuranyl, oxadiazolyl, diazolylpyridinyl,        imidazolylpyridinyl, oxadiazolylphenyl, or benzodioxolyl;    -   R₁ is hydrogen, halogen; or —C₁₋₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —H, —CN, or —SO₂—C₁₋₆alkyl;    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, —NO₂; or —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₁₋₆alkyl(C₂₋₆alkenyl)₂, C₀₋₄alkyl(C₃₋₆cycloalkyl)₂,        —C₀₋₆alkyl-N(C₀₋₆alkyl)₂, —C₀₋₄alkyl-O—C₁₋₆alkyl,        —C₁₋₆alkyl-phenyl, —C₀₋₆alkyl-SO₂—C₁₋₆alkyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl, —C₀₋₆alkyl-C(O) C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkylC₀₋₆alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₄alkyl-C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₆alkyl)pyridyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        —SO₂—C₀₋₆alkyl-(—C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        —S(O)—C₀₋₆alkyl, —P(O)(O—C₀₋₄alkyl)(O—C₀₋₄alkyl),        C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)-pyridyl, —S—C₁₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)C₀₋₆alkyl, —C₀₋₆alkyl-N(C₀₋₆alkyl)        C(O)—N(C₀₋₆alkyl)₂, —C₀₋₄alkyl-S—C        14alkyl-oxadiazolyl(C₀₋₄alkyl), C₀₋₄alkyl-C(O)C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl diazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₁₋₄alkyl-Si(C₀₋₄alkyl)₃,        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C₀₋₄alkyl-O—C₁₋₆alkyl, or —C₀₋₄alkyl-S—C₁₋₆alkyl;    -   optionally, R₂ forms ═O with an adjoining bond;    -   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In one aspect, the compound of this invention is represented by Formula(1), or a pharmaceutically acceptable salt thereof, wherein.

-   -   A is C;    -   X is phenyl, pyridyl, pyrazinyl, thiaphenyl, quinolinyl,        benzofuranyl, oxadiazolyl, diazolylpyridinyl,        imidazolylpyridinyl, oxadiazolylphenyl, or benzodioxolyl;    -   R₁ is hydrogen, halogen; or —C₁₋₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —OH, —CN, or —SO₂—C₁₋₆alkyl;    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, —NO₂; or —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₁₋₁₆alkyl(C₂₋₆alkenyl)₂, —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂,        —C₀₋₆alkyl-N(C₀₋₆alkyl)₂, —C₀₋₄alkyl-O—C₁₋₆alkyl,        —C₁₋₆alkyl-phenyl, —C₀₋₆alkyl-SO₂—C₁₋₆alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl, —C₀₋₆alkyl-C(O) C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₆alkyl-C(O)C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₆alkyl)-pyridyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        —SO₂—C₀₋₆alkyl-(—C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        —S(O)—C₀₋₆alkyl, —P(O)(O—C₀₋₄alkyl)(O—C₀₋₄alkyl),        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)-pyridyl, S—C₁₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—C₀₋₆alkyl, —C₀₋₆alkyl-N(C₀₋₆alkyl)        C(O)N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-S—C₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₁₋₄alkyl-Si(C₀₋₄alkyl)₃,        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-S—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C₀₋₄alkyl-O—C₁₋₆alkyl, or —C₀₋₄alkyl-S—C₁₋₆alkyl;    -   optionally, R₂ forms ═0 with an adjoining bond;    -   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In an embodiment of this one aspect, the compound of this invention is,represented by Formula (I), or a pharmaceutically acceptable saltthereof, wherein

-   -   A is C;    -   X is phenyl;    -   R₁ is hydrogen, halogen; or —C₁₋₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —OH, —CN, or —SO₂—C₁₋₆alkyl;    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, —NO₂; or —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₁₋₆alkyl(C₂₋₆alkenyl)₂, —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂,        —C₀₋₆alkyl-N(C₀₋₆alkyl)₂, —C₀₋₄alkyl-O—C₁₋₆alkyl,        —C₁₋₆alkyl-phenyl, —C₀₋₆alkyl-SO₂—C₁₋₆alkyl,        C₀₋₆alkyl-C(O)—C₀₋₄alkyl, —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₆alkyl-C(O)C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₆alkyl)-pyridyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        —SO₂—C₀₋₆alkyl-(—C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —7C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        —S(O)—C₀₋₆alkyl, —P(O)(O—C₀₋₄alkyl)(O—C₀₋₄alkyl),        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)-pyridyl, —S—C₁₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—C₀₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-S—₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),        C₀₋₄alkyl-S—₁₋₄alkyl-Si(C₀₋₄alkyl)₃,        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-S—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl(O)C₀₋₄alkyl-O—C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C₀₋₄alkyl-O—C₁₋₆alkyl, or C₀₋₄alkyl-S—₁₋₆alkyl;    -   optionally, R₂ forms ═O with an adjoining bond;    -   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In another embodiment of this one aspect, the compound of this inventionis represented by Formula (I), or a pharmaceutically acceptable saltthereof, wherein

-   -   A is C;    -   X is thiaphenyl;    -   R₁ is hydrogen, halogen; or —C₁₋₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —OH, —CN, or —SO₂—C₁₋₆alkyl;    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, —NO₂; or —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₁₋₆alkyl(C₂₋₆alkenyl)₂, —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂,        —C₀₋₆alkyl-N(C₀₋₆alkyl)₂, —C₀₋₄alkyl-O—C₁₋₆alkyl,        —C₁₋₆alkyl-phenyl, —C₀₋₆alkyl-SO₂—C₁₋₆alkyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl, —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl-C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₆alkyl)-pyridyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        SO₂—C₀₋₆alkyl-(—C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl,        —S(O)C₀₋₆alkyl, —P(O)(O—C₀₋₄alkyl)(O—C₀₋₄alkyl),        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)-pyridyl, —S—₁₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—C₀₋₆alkyl-C₀₋₆alkyl-N(C₀₋₆alkyl)        C(O)N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-S—C₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₆alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyldiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₁₋₄alkyl-Si(C₀₋₄alkyl)₃,        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-C(O). C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-S—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C₀₋₄alkyl-O—C₁₋₆alkyl, or —C₀₋₄alkyl-S—C₁₋₆alkyl;    -   optionally, R₂ forms ═O with an adjoining bond;    -   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In still another embodiment of this one aspect, the compound of thisinvention is represented by Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein

-   -   A is C;    -   X is benzofuranyl;    -   R₁ is hydrogen, halogen; or —C₁₋₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —OH, —CN, or —SO₂—C₁₋₆alkyl;    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, —NO₂; or —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₁₋₆alkyl(C₂₋₆alkenyl)₂, —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂,        —C₀₋₆alkyl-N(C₀₋₆alkyl)₂, —C₀₋₄alkyl-O—C₁₋₆alkyl,        —C₁₋₆alkyl-phenyl, —C₀₋₆alkyl-SO₂—C₁₋₆alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl, —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₆alkyl)pyridyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        —SO₂—C₀₋₆alkyl-(—C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-C₀₋₄alkyl,        —S(O)—C₀₋₆alkyl, —P(O)(O)—C₀₋₄alkyl)(O—C₀₋₄alkyl),        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)-pyridyl, —S—₁₋₆alkyl,        C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)C₀₋₆alkyl, —C₀₋₆alkyl-N(C₀₋₆alkyl)        C(O)N(C₀₋₆alkyl)₂, —C₀₋₄alkyl-C₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-phenyl, C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—₁₋₄alkyl-Si(C₀₋₄alkyl)₃,        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C₀₋₄alkyl-C₁₋₆alkyl, or —C₀₋₄alkyl-S—₁₋₆alkyl;    -   optionally, R₂ forms ═O with an adjoining bond;    -   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In yet another embodiment of this one aspect, the compound of thisinvention is represented by Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein

-   -   A is C;    -   X is pyridyl;    -   R₁ is hydrogen, halogen; or —C₁₋₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —OH, —CN, or —SO₂—C₁₋₆alkyl;    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, —NO₂; or —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₁₋₆alkyl(C₂₋₆alkenyl)₂, —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂,        —C₀₋₆alkyl-N(C₀₋₆alkyl)₂, —C₀₋₄alkyl-C₁₋₆alkyl,        —C₁₋₆alkyl-phenyl, —C₀₋₆alkyl-SO₂—C₁₋₆alkyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl, —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₆alkyl-C(O)C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₆alkyl)-pyridyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        —SO₂—C₀₋₆alkyl-(—C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        —S(O)C₀₋₆alkyl, —P(O)(O-C ₀₋₄alkyl)(O—C₀₋₄alkyl),        C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)pyridyl, —S—₁₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—C₀₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-S—₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl), —C₀₋₄alkyl-C(O)        C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₁₋₄alkyl-Si(C₀₋₄alkyl)₃,        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-S—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C ₀₋₆alkyl-O—C₁₋₆alkyl, or —C₀₋₄alkyl-S—₁₋₆alkyl;    -   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In yet still another embodiment of this one aspect, the compound of thisinvention is represented by Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein

-   -   A is C;    -   X is pyridyl;    -   R₁ is hydrogen, halogen; or —C₁₋₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —OH, —CN, or —SO₂—C₁₋₆alkyl;    -   R₃ is hydrogen, halogen, hydroxyl, —CN, —NO₂; or —C₁₋₆alkyl,        —C₂₋₆alkenyl, —C₁₋₁₆alkyl(C₂₋₆alkenyl)₂,        —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂, —C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-phenyl,        —C₀₋₆alkyl-SO₂—C₁₋₆alkyl, —C₀₋₆alkyl-C(O)—C₀₋₄alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₆alkyl-C(O)C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₄alkyl C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₆alkyl)-pyridyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        —SO₂—C₀₋₆alkyl-(—C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl(O)C₀₋₄alkyl-O—C₀₋₄alkyl,        —S(O)C₀₋₆alkyl, —P(O)(O—C₀₋₄alkyl)(O—C₀₋₄alkyl),        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)-pyridyl, —S—C₁₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)C₀₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-S—C₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),        C₀₋₄alkyl-S—C₁₋₄alkyl-Si(C₀₋₄alky)₃,        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-C(O—C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-S—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C₀₋₄alkyl-O—C₁₋₆alkyl, or —C₀₋₄alkyl-S—C₁₋₆alkyl;    -   R₂ forms ═O with an adjoining bond;    -   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In still another embodiment of this one aspect, the compound of thisinvention is represented by Formula (1), or a pharmaceuticallyacceptable salt thereof, wherein

-   -   A is C;    -   X is quinolinyl;    -   R₁ is hydrogen, halogen; or —C₁₋₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —OH, —CN, or —SO₂—C₁₋₆alkyl;    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, —NO₂; or —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₁₋₆alkyl(C₂₋₆alkenyl)₂, —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂,        —C₀₋₆alkyl-N(C₀₋₆alkyl)₂, —C₀₋₄alkyl)—C₁₋₆alkyl,        —C₁₋₆alkyl-phenyl, —C₀₋₆alkyl-SO₂—C₁₋₆alkyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl, —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₆alkyl-C(O)C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl, —C₀₋₄alkyl-C        ₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₆alkyl)pyridyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        —SO₂—C₀₋₆alkyl-(—C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        —S(O)C₀₋₆alkyl, —P(O)(O—C₀₋₄alkyl)(O—C₀₋₄alkyl),        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)pyridyl, —S—₁₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—C₀₋₆alkyl—C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-S—C₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—₁₋₄alkyl-Si(C₀₋₄alkyl)₃,        —C₀₋₄alkyl-C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-S—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C₀₋₄alkyl-O—C₁₋₆alkyl, or —C₀₋₄alkyl-S—C ₁₋₆alkyl;    -   optionally, R₂ forms ═O with an adjoining bond;    -   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In still another embodiment of this one aspect, the compound of thisinvention is represented by Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein A is C;

-   -   X is oxadiazolyl;    -   R₁ is hydrogen, halogen; or —C₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —H, —CN, or —SO₂—C₁₋₆alkyl;    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, —NO₂; or —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₁₋₁₆alkyl(C₂₋₆alkenyl)₂, —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂,        —C₀₋₆alkyl-N(C₀₋₆alkyl)₂, —C₀₋₄alkyl-O—C₁₋₆alkyl,        —C₁₋₆alkyl-phenyl, —C₀₋₆alkyl-SO₂—C₁₋₆alkyl,        —C₀₋₆alkyl(O)C₀₋₄alkyl, —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₆alkyl-C(O)C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)C₀₋₆alkyl,        C₂₋₆alkenyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₆alkyl)-pyridyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        —SO₂—C₀₋₆alkyl-(—C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        S(O)—C₀₋₆alkyl, —P(O)(O—C₀₋₄alkyl)(0C₀₋₄alkyl),        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)pyridyl, —S—₁₋₆alkyl,        C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—C₀₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-S—C₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-C(O)C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),        C₀₋₄alkyl-S—C₁₋₄alkyl-Si(C₀₋₄alkyl)₃,        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl(O)—C₀₋₄alkyl-C₀₋₄alkyl, or        —C₀₋₄alkyl-S—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)C₀₋₄alkyl-C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C₀₋₄alkyl-O—C₁₋₆alkyl, or —C₀₋₄alkyl-S—C₁₋₆alkyl;    -   optionally, R₂ forms ═O with an adjoining bond;    -   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In yet another embodiment of this one aspect, the compound of thisinvention is represented by Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein

-   -   A is C;    -   X is diazolylpyridinyl or imidazolylpyridinyl;    -   R₁ is hydrogen, halogen; or C₁₋₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —OH, N, or —SO₂—C₁₋₆alkyl;    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, —NO₂; or —C₁₋₆alkyl, C₂₋₆alkenyl, —C₁₋₆alkyl(C₂₋₆alkenyl)₂,        —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂, —C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-phenyl,        —C₀₋₆alkyl-SO₂—C₁₋₆alkyl, —C₀₋₆alkyl-C(O)—C₀₋₄alkyl,        C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₆alkyl-C(O)C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl-C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₆alkyl)pyridyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        —SO₂C₀₋₆alkyl-(C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        —S(O)—C₀₋₆alkyl, —P(O)(O—C₀₋₄alkyl)(O—C₀₋₄alkyl),        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)pyridyl, —S—C₁₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—C₀₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-S—₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl), C₀₋₄alkyl-S        —C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),        C₀₋₄alkyl-S—₁₋₄alkyl-Si(C₀₋₄alkyl)₃,        —C₀₋₄alkyl-O—C-₀₋₄alkyl-phenyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-S—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C₀₋₄alkyl-C₁₋₆alkyl, or C₀₋₄alkyl-SC₁₋₆alkyl;    -   optionally, R₂ forms ═O with an adjoining bond;    -   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In still another embodiment of this one aspect, the compound of thisinvention is represented by Formula (1), or a pharmaceuticallyacceptable salt thereof, wherein

A is C;

-   -   X is pyrazinyl;    -   R₁ is hydrogen, halogen; or —C₁₋₆alkyl, -cycloC₃₋₆alkyl; or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —OH, —CN, or —SO₂—C₁₋₆alkyl;    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, NO₂; or —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl(C₂₋₆alkenyl)₂,        —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂, —C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-henyl,        —C₀₋₆alkyl-SO₂—C₁₋₆alkyl, —C₀₋₆alkyl-C(O)—C₀₋₄alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₆alkyl)pyridyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        —SO₂—C₀₋₆alkyl-(—C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        —S(O)—C₀₋₆alkyl, —P(O)(O—C₀₋₄alkyl)(O—C₀₋₄alkyl),        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)pyridyl, —S—₁₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)C₀₋₆alkyl-C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-S—C₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—₁₋₄alkyl-Si(C₀₋₄alkyl)₃,        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-S—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C₀₋₄alkyl-O—C₁₋₆alkyl, or —C₀₋₄alkyl-S—C₁₋₆alkyl;    -   optionally, R₂ forms ═O with an adjoining bond;    -   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In yet still another embodiment of this one aspect, the compound of thisinvention is represented by Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein

-   -   A is C;    -   X is oxadiazolylphenyl;    -   R₁ is hydrogen, halogen; or C₁₋₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —OH, —CN, or —SO₂—C₁₋₆alkyl,    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, —NO₂; or —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₁₋₆alkyl(C₂₋₆alkenyl)₂, —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂,        —C₀₋₆alkyl-N(C₀₋₆alkyl)₂, —C₀₋₄alkyl-O—C₁₋₆alkyl,        C₁₋₆alkyl-phenyl, C₀₋₆alkyl-SO₂—C₁₋₆alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl, —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl-C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₆alkyl)-pyridyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        O₂—C₀₋₆alkyl-C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl        C₀₋₄alkyl-C(O)—C₀₋₄alkyl-S—C₀₋₄alkyl S(O)—C₀₋₆alkyl,        —P(O)(O—C₀₋₄alkyl)(O—C₀₋₄alkyl),        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)-pyridyl, —S—₁₋₆alky,        alkyl-C(O)—C₀₋₆alkyl, —C₀₋₆alkyl-N(C₀₋₆alkyl)        C(O)—N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-S—C₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl)—C₀₋₄alkyl-SC₀₋₄alkyl-diazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-Si(C₀₋₄alkyl)₃,        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-S—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, C₀₋₄alkyl-O—C₁₋₆alkyl or —C₀₋₄alkyl-S—₁₋₆alkyl;    -   optionally, R₂ forms ═O with an adjoining bond;

R₄ is hydrogen, or halogen; and

-   -   any ring nitrogen optionally forms N-oxide or N-chloride,

In even another embodiment of this one aspect, the compound of thisinvention is represented by Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein.

A is C;

-   -   X is benzodioxolyl;    -   R₁ is hydrogen, halogen; or —C₁₋₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —OH, —CN, or —SO₂—C₁₋₆alkyl;    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, —NO₂; or —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₁₋₆alkyl(C₂₋₆alkenyl)₂, —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂,        —C₀₋₆alkyl-N(C₀₋₆alkyl)₂, —C₀₋₄alkyl-O—C₁₋₆alkyl,        —C₁₋₆alkyl-phenyl, —C₀₋₆alkyl-SO₂—C₁₋₆alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl, —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)_C₀₋₄alkyl-O—C₀₋₆alkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₆alkyl)-pyridyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        —SO₂—C₀₋₆alkyl-(—C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        —S(O)—C₀₋₆alkyl, —P(O)(O—C₀₋₄alkyl)(O—C₀₋₄alkyl),        C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)-pyridyl, —S—₁₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—C₀₋₆alkyl, —C₀₋₆alkyl-N(C₀₋₆alkyl)        C(O)—N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-S—₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₁₋₄alkyl-Si (C₀₋₄alkyl)₃,        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-S—C₀₋₄alky-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C₀₋₄alkyl-O—C₁₋₁₆alkyl, or —C₀₋₄alkyl-S—₁₋₆alkyl;    -   optionally, R₂ forms ═O with an adjoining bond;    -   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In a second aspect, the compound of this invention is represented byFormula (I, or a pharmaceutically acceptable salt thereof, wherein

-   -   A is N;    -   X is phenyl, pyridyl, pyrazinyl, thiaphenyl, quinolinyl,        benzofuranyl, oxadiazolyl, diazolylpyridinyl,        imidazolylpyridinyl, oxadiazolylphenyl, or benzodioxolyl;    -   R₁ is hydrogen, halogen; or —C₁₋₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —OH, —CN, or —SO₂—C₁₋₆alkyl;    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, —NO₂; or —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₁₋₆alkyl(C₂₋₆alkenyl)₂, —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂,        —C₀₋₆alkyl-N(C₀₋₆alkyl)₂, —C₀₋₄alkyl-O—C₁₋₆alkyl,        —C₁₋₆alkyl-phenyl, —C₀₋₆alkyl-SO₂—C₁₋₆alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl, —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₆alkyl)-pyridyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —C₂₋₆alkenyl(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        SO₂—C₀₋₆alkyl-phenyl, —SO₂—C₀₋₆alkyl-        C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl,        —S(O)—C₀₋₆alkyl, —P(O)(O—C₀₋₄alkyl)(O—C₀₋₄alkyl),        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)pyridyl, —S—₁₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—N(C₀₋₆alkyl)₂,        C₀₋₄alkyl-S—C₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl), —C₀₋₄alkyl-C(O)C        ₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        O₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—₁₋₄alkyl-Si(C₀₋₄alkyl)₃,        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-S—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C₀₋₄alkyl-O—C₁₋₆alkyl, or —C₀₋₄alkyl-S—C₁₋₆alkyl;    -   optionally, R₂ forms ═O with an adjoining bond;

-   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In an embodiment of the second aspect, the compound of this invention isrepresented by Formula (I), or a pharmaceutically acceptable saltthereof, wherein

-   -   A is N;    -   X is phenyl;    -   R ₁ is hydrogen, halogen; or —C₁₋₆alkyl, -cycloC₃₋₆alkyl, or        —C₁₋₆alkenyl group, wherein any of the groups is optionally        substituted with 1-6 substituents; wherein each substituent is        independently halogen, —OH, —CN, or —SO₂—C₁₋₆alkyl;    -   R₂, and R₃ are each independently hydrogen, halogen, hydroxyl,        —CN, —NO₂; or —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₁₋₆alkyl(C₂₋₆alkenyl)₂, —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂,        —C₀₋₆alkyl-N(C₀₋₆alkyl)₂, —C₀₋₄alkyl-O—C₁₋₆alkyl,        —C₆alkyl-phenyl, —C₀₋₆alkyl-SO₂—C₁₋₆alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₄alkyl, —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl-N(C₀₋₆alkyl)₂,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₆alkyl)pyridyl,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)₂,        —C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        C₂₋₆alkenyl(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,        —SO₂—C₀₋₆alkyl-phenyl,        —SO₂—C₀₋₆alkyl-4-C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₀₋₄alkyl-SO₂C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl,        —S(O)—C₀₋₆alkyl, —P(O)(O—C₀₋₄alkyl)(0C₀₋₄alkyl),        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)-pyridyl, —S—₁₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—C₀₋₆alkyl,        —C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)N(C₀₋₆alkyl)₂,        C₀₋₄alkyl-S—₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-C(O)—C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —SO₂—N(C₀₋₄alkyl)₂,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₁₋₄alkyl-Si(C₀₋₄alkyl)₃,        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl, or        —C₀₋₄alkyl-S—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,        wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are        each optionally substituted with 1-9 independently halogen,        hydroxyl, —C₀₋₄alkyl-O—C₁₋₆alkyl, or —C₀₋₄alkyl-S—₁₋₆alkyl;        optionally, R₂ forms ═O with an adjoining bond;    -   R₄ is hydrogen, or halogen; and    -   any ring nitrogen optionally forms N-oxide or N-chloride.

In one aspect, R₂, and R₃ are each independently hydrogen, halogen,hydroxyl, —CN, or —NO₂.

In another aspect, R₂, and R₃ are each independently-C₁₋₆alkyl,—C₂₋₆alkenyl, —C₁₋₆alkyl(C₂₋₆alkenyl)₂, or —C₀₋₄alkyl(C₃₋₆cycloalkyl)₂,wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are eachoptionally substituted with 1-9 independently halogen, hydroxyl,—C₀₋₄alkyl-O—C₁₋₆alkyl, or —C₀₋₄alkyl-S—₁₋₆alkyl.

In another aspect, R₂, and R₃ are each independently—C₀₋₆alkyl-N(C₀₋₆alkyl)₂,C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl-N(C₀₋₆alkyl)₂,—C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₆alkyl)pyridyl,—C₀₋₆alkyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)₂,—C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,—C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl—C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)pyridyl,—C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—C₀₋₆alkyl, —C₀₋₆alkyl-N(C₀₋₆alkyl)C(O)N(C₀₋₆alkyl)₂, or —SO—N(C₀₋₄alkyl)₂, wherein any alkyl, cycloalkyl,alkenyl, phenyl, or pyridyl are each optionally substituted with 1-9independently halogen, hydroxyl, —C₀₋₄alkyl-O—C₁₋₆alkyl, or—C₀₋₄alkyl-S—₁₋₆alkyl.

In another aspect, R₂, and R₃ are each independently—C₀₋₆alkyl-SO₂—C₁₋₆alkyl-SO₂—C₀₋₆alkyl-phenyl,—SO₂—C₀₋₆alkyl-(—C₀₋₆alkylphenyl)(—C ₀₋₆alkyl-phenyl),—C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,(O)C₀₋₆alkyl, -S—C₁₋₆alkyl,—C₀₋₄alkyl-S—C₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl), —SO₂—N(C₀₋₄alkyl)₂,—C₀₋₄alkyl-C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl), —C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),—C₀₋₄alkyl-S—₁₋₄alkyl-Si(C₀₋₄alkyl)₃,—C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),—C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl, or—C₀₋₄alkyl-S—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl,wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are eachoptionally substituted with 1-9 independently halogen, hydroxyl,—C₀₋₄alkyl-O—C₁₋₆alkyl, or —C₀₋₄alkyl-S—C₁₋₆alkyl.

In an aspect, R₂ forms ═O with an adjoining bond;

-   -   In another aspect, R₂ and R₃ are each independently        —C₁₋₆alkyl-phenyl, —C₀₋₆alkyl-C(O)—C₀₋₆alkyl-phenyl,        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₆alkyl)pyridyl,        —SO₂—C₀₋₆alkyl-phenyl,        —SO₂—C₀₋₆alkyl-(—C₀₋₆alkyl-phenyl)(—C₀₋₆alkyl-phenyl),        —C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)pyridyl,        —C₀₋₄alkyl-S—₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-C(O)C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,        —C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl,        —C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),        —C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl), or        —C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl), wherein any alkyl,        cycloalkyl, alkenyl, phenyl, or pyridyl are each optionally        substituted with 1-9 independently halogen, hydroxyl,        —C₀₋₄alkyl-O—C₁₋₆alkyl, or —C₀₋₄alkyl-S—₁₋₆alkyl.

In another aspect, the present invention is directed to a method ofenhancing cognition in a healthy subject comprising administering a safecognition enhancing amount of a phosphodiesterase-4 inhibitor. Inparticular, this invention is directed to a method of enhancing memory,learning, retention, recall, awareness and judgement in health subjectscomprising administering a safe and cognition enhancing amount of aphosphodiesterase-4 inhibitor. Within this aspect there is a method ofenhancing cognition in a healthy subject comprising administering asafe, non-emetic, cognition enhancing amount of a phosphodiesterase-4inhibitor

For purposes of this application is defined as a subject with cognitionin the normal range for the subjects age or other classification.Cognition of a healthy subject as well as cognition enhancement of thehealthy subject is illustrated shown by testing the compounds in theMorris water maze as reported by McNamara and Skelton, Psychobiology,1993, 21, 101-108. Further details of relevant methodology are describedin WO 96/25948. Other assessments for measuring cognition enhancementinclude, but are not limited to the “T” Maze Test; Radial Arm Maze Test;Delayed Non-Match or Delayed Match Test; Passive Avoidance Procedure; 5Choice Test, disclosed in WO 01/87281 A2, published Nov. 22, 2001.

For purposes of this specification, classes of healthy subjects includesjuveniles, adults and seniors of average cognition; juveniles, adultsand seniors of above average cognition; and juveniles, adults andseniors of below average cognition.

For purposes of this specification, juvenile human subjects is definedas a human subject less than 18 years of age. For purposes of thisspecification, adult human subject is defined as a human subject 18years of age or older. Within this classification is a human adult 18 to40 years of age. For purposes of this specification, senior humansubjects is defined as a human subject 40 years of age or older. Withinthis classification is a human subject 55 years of age or older; 65years of age or older; and 70 years of age or older.

As appreciated by those of skill in the art, beginning at about age 25,the cognition of the healthy human declines at a measurable andreproducible rates, as for example, measured by CAmbridgeNeuropsychological Test Automated Battery (CANTAB, de Jager C A, MilwainE, Budge M. Early detection of isolated memory deficits in the elderly:the need for more sensitive neuropsychological tests. Psychol Med 2002April; 32(3):483-91) or the Cognitive Drug Reseach Battery (CDR, BarkerA, Jones R, Simpson P, Wesnes K. (1995). Scopolamine induced cognitiveimpairment as a predictor of cognitive decline in healthy elderlyvolunteers. International Journal of Geriatric Psychiatry 10:1059-1062). Thus, by the time a human subject becomes a senior 40 yearsof age the decline in cognitive function has declined significant andwould benefit from a method of memory enhancement.

As used herein, “alkyl” as well as other groups having the prefix “alk”such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like,means carbon chains which may be linear or branched or combinationsthereof. Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and thelike. “Alkenyl”, “alkynyl” and other like terms include carbon chainscontaining at least one unsaturated C—C bond.

The term “cycloalkyl” means carbocycles containing no heteroatoms, andincludes mono-, bi- and tricyclic saturated carbocycles, as well asfused ring systems. Such fused ring systems can include one ring that ispartially or fully unsaturated such as a benzene ring to form fused ringsystems such as benzofused carbocycles. Cycloalkyl includes such fusedring systems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalenyl,adamantanyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalenyland the like. Similarly, “cycloalkenyl” means carbocycles containing noheteroatoms and at least one non-aromatic C—C double bond, and includemono-, bi- and tricyclic partially saturated carbocycles, as well asbenzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,indenyl, and the like.

The term “cycloalkyloxy” unless specifically stated otherwise includes acycloalkyl group connected to the oxy connecting atom.

The term “alkoxy” unless specifically stated otherwise includes an alkylgroup connected to the oxy connecting atom.

The term “aryl” unless specifically stated otherwise includes multiplering systems as well as single ring systems such as, for example, phenylor naphthyl. The term “aryloxy” unless specifically stated otherwiseincludes multiple ring systems as well as single ring systems such as,for example, phenyl or naphthyl, connected through the oxy connectingatom to the connecting site.

The term “C₀-C₆alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or nocarbon atoms. An alkyl with no carbon atoms is a hydrogen atomsubstituent when the alkyl is a terminus moiety. An alkyl with no carbonatoms is a direct bond when the alkyl is a bridging moiety.

The term “hetero” unless specifically stated otherwise includes one ormore O, S, or N atoms. For example, heterocycloalkyl and heteroarylinclude ring systems that contain one or more O, S, or N atoms in thering, including mixtures of such atoms. The heteroatoms replace ringcarbon atoms. Thus, for example, a heterocycloC₅alkyl is a five memberedring containing from 5 to no carbon atoms.

Examples of heteroaryl include, for example, pyridinyl, quinolinyl,isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl,benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl,pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl.

The term “heteroaryloxy” unless specifically stated otherwise describesa heteroaryl group connected through an oxy connecting atom to theconnecting site.

Examples of heteroaryl(C₁₋₆)alkyl include, for example, furylmethyl,furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl,oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl,thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl,oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl,thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl,tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl,isoquinolinylmethyl and quinoxalinylmethyl.

Examples of heterocycloC₃₋₇alkyl include, for example, azetidinyl,pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl, morpholinyl,tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, andthiomorpholinyl.

The term “N-heterocycloC₄₋₇alkyl” describes nonaryl heterocycliccompounds having 3-6 carbon atoms and one nitrogen atom forming thering. Examples include azetidinyl, pyrrolidinyl, piperidinyl, andperhydroazepinyl.

Examples of aryl(C₁₋₆)alkyl include, for example, phenyl(C₁₋₆)alkyl, andnaphthyl(C₁₋₆)alkyl.

Examples of heterocycloC₃₋₇alkylcarbonyl(C₁₋₆)alkyl include, forexample, azetidinyl carbonyl(C₁₋₆)alkyl, pyrrolidinylcarbonyl(C₁₋₆)alkyl, piperidinyl carbonyl(C₁₋₆)alkyl, piperazinylcarbonyl(C₁₋₆)alkyl, morpholinyl carbonyl(C₁₋₁)alkyl, andthiomorpholinyl carbonyl(C₁₋₆)alkyl.

The term “amine” unless specifically stated otherwise includes primary,secondary and tertiary amines.

Unless otherwise stated, the term “carbamoyl” is used to include—NHC(O)OC₁-C₄alkyl, and —OC(O)NHC₁-C₄alkyl.

The term “halogen” includes fluorine, chlorine, bromine and iodineatoms.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further, thesubstitution can be made at any of the groups. For example, substitutedaryl(C₁₋₆)alkyl includes substitution on the aryl group as well assubstitution on the alkyl group.

The term “oxide” of heteroaryl groups is used in the ordinary well-knownchemical sense and include, for example, N-oxides of nitrogenheteroatoms.

Compounds described herein contain one or more double bonds and may thusgive rise to cis/trans isomers as well as other conformational isomers.The present invention includes all such possible isomers as well asmixtures of such isomers.

Compounds described herein can contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be mixtures of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediainine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucarine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are benzenesulfonic, citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula I (or pharmaceutically acceptable saltsthereof) as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Suchadditional therapeutic ingredients include, for example, i) Leukotrienereceptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii)corticosteroids, iv) H1 receptor antagonists, v) beta 2 adrenoceptoragonists, vi) COX-2 selective inhibitors, vii) statins, viii)non-steroidal anti-inflammatory drugs (“NSAID”), and ix) M2/M3antagonists. The compositions include compositions suitable for oral,rectal, topical, and parenteral (including subcutaneous, intramuscular,and intravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions may be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Creams, ointments, jellies, solutions, or suspensions containing thecompound of Formula I can be employed for topical use. Mouth washes andgargles are included within the scope of topical use for the purposes ofthis invention.

Dosage levels from about 0.001 mg/kg to about 140 mg/kg of body weightper day are useful in the treatment of conditions such as i) Pulmonarydisorders such as asthma, chronic bronchitis, chronic obstructivepulmonary disease (COPD), adult respiratory distress syndrome, infantrespiratory distress syndrome, cough, chronic obstructive pulmonarydisease in animals, adult respiratory distress syndrome, and infantrespiratory distress syndrome, ii) Gastrointestinal disorders such asulcerative colitis, Crohn's disease, and hypersecretion of gastric acid,iii) Infectious diseases such as bacterial, fungal or viral inducedsepsis or septic shock, endotoxic shock (and associated conditions suchas laminitis and colic in horses), and septic shock, iv) Neurologicaldisorders such as spinal cord trauma, head injury, neurogenicinflammation, pain, and reperfusion injury of the brain, v) Inflammatorydisorders such as psoriatic arthritis, rheumatoid arthritis, ankylosingspondylitis, osteoarthritis, inflammation and cytokine-mediated chronictissue degeneration, vi) Allergic disorders such as allergic rhinitis,allergic conjunctivitis, and eosinophilic granuloma, vii) Psychiatricdisorders such as depression, memory impairment, and monopolardepression, viii) Neurodegenerative disorders such as Parkinson disease,Alzheimer's disease, acute and chronic multiple sclerosis, ix)Dermatological disorders such as psoriasis and other benign or malignantproliferative skin diseases, atopic dermatitis, and urticaria, x)Oncological diseases such as cancer, tumor growth and cancerous invasionof normal tissues, xi) Metabolic disorders such as diabetes insipidus,xii) Bone disorders such as osteoporosis, xiii) Cardiovascular disorderssuch as arterial restenosis, atherosclerosis, reperfusion injury of themyocardium, and xiv) Other disorders such as chronic glomerulonephritis,vernal conjunctivitis, transplant rejection and graft versus hostdisease, and cachexia—which are responsive to PDE4 inhibition, oralternatively about 0.05 mg to about 7 g per patient per day. Forexample, inflammation may be effectively treated by the administrationof from about 0.01 mg to 50 mg of the compound per kilogram of bodyweight per day, or alternatively about 0.5 mg to about 2.5 g per patientper day. Further, it is understood that the PDE4 inhibiting compounds ofthis invention can be administered at prophylactically effective dosagelevels to prevent the above-recited conditions.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient, amount of carriermaterial which may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about0.01 mg to about 1000 mg of the active ingredient, typically 0.00 mg,0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

In practice, the compounds represented by Formula I, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compound represented byFormula I, or pharmaceutically acceptable salts thereof, may also beadministered by controlled release means and/or delivery devices. Thecompositions may be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula I. The compounds of Formula I, orpharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or pharmaceutically acceptable saltsthereof, via conventional processing methods. As an example, a cream orointment is prepared by mixing hydrophilic material and water, togetherwith about 5 wt % to about 10 wt % of the compound, to produce a creamor ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

The compounds and pharmaceutical compositions of this invention havebeen found to exhibit biological activity as PDE4 inhibitors.Accordingly, another aspect of the invention is the treatment in mammalsof, for example, i) Pulmonary disorders such as asthma, chronicbronchitis, chronic obstructive pulmonary disease (COPD), adultrespiratory distress syndrome, infant respiratory distress syndrome,cough, chronic obstructive pulmonary disease in animals, adultrespiratory distress syndrome, and infant respiratory distress syndrome,ii) Gastrointestinal disorders such as ulcerative colitis, Crohn'sdisease, and hypersecretion of gastric acid, iii) Infectious diseasessuch as bacterial, fungal or viral induced sepsis or septic shock,endotoxic shock (and associated conditions such as laminitis and colicin horses), and septic shock, iv) Neurological disorders such as spinalcord trauma, head injury, neurogenic inflammation, pain, and reperfusioninjury of the brain, v) Inflammatory disorders such as psoriaticarthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis,inflammation and cytokine-mediated chronic tissue degeneration, vi)Allergic disorders such as allergic rhinitis, allergic conjunctivitis,and eosinophilic granuloma, vii) Psychiatric disorders such asdepression, memory impairment, and monopolar depression, viii)Neurodegenerative disorders such as Parkinson disease, Alzheimer'sdisease, acute and chronic multiple sclerosis, ix) Dermatologicaldisorders such as psoriasis and other benign or malignant proliferativeskin diseases, atopic dermatitis, and urticaria, x) Oncological diseasessuch as cancer, tumor growth and cancerous invasion of normal tissues,xi) Metabolic disorders such as diabetes insipidus, xii) Bone disorderssuch as osteoporosis, xiii) Cardiovascular disorders such as arterialrestenosis, atherosclerosis, reperfusion injury of the myocardium, andxiv) Other disorders such as chronic glomerulonephritis, vernalconjunctivitis, transplant rejection and graft versus host disease, andcachexia—maladies that are amenable to amelioration through inhibitionof the PDE4 isoenzyme and the resulting elevated cAMP levels—by theadministration of an effective amount of the compounds of thisinvention. The term “mammals” includes humans, as well as other animalssuch as, for example, dogs, cats, horses, pigs, and cattle. Accordingly,it is understood that the treatment of mammals other than humans is thetreatment of clinical correlating afflictions to those above recitedexamples that are human afflictions.

Further, as described above, the compound of this invention can beutilized in combination with other therapeutic compounds. In particular,the combinations of the PDE4 inhibiting compound of this invention canbe advantageously used in combination with i) Leukotriene receptorantagonists, ii) Leukotriene biosynthesis inhibitors, iii) COX-2selective inhibitors, iv) statins, v) NSAIDs, vi) M2/M3 antagonists,vii) corticosteroids, viii) H1 (histamine) receptor antagonists and ix)beta 2 adrenoceptor agonist.

Thus, for example, pulmonary disorders such as asthma, chronicbronchitis, chronic obstructive pulmonary disease (COPD), adultrespiratory distress syndrome, infant respiratory distress syndrome,cough, chronic obstructive pulmonary disease in animals, adultrespiratory distress syndrome, and infant respiratory distress syndromecan be conveniently treated with capsules, cachets or tablets eachcontaining 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or500 mg of the active ingredient of the compound of the presentapplication, or a pharmaceutically acceptable salt thereof, administeredonce, twice, or three times daily.

Gastrointestinal disorders such as ulcerative colitis, Crohn's disease,and hypersecretion of gastric acid can be conveniently treated withcapsules, cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient ofthe compound of the present application, or a pharmaceuticallyacceptable salt thereof, administered once, twice, or three times daily.

Infectious diseases such as bacterial, fungal or viral induced sepsis orseptic shock, endotoxic shock (and associated conditions such aslaminitis and colic in horses), and septic shock can be convenientlytreated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the activeingredient of the compound of the present application, or apharmaceutically acceptable salt thereof, administered once, twice, orthree times daily.

Neurological disorders such as spinal cord trauma, head injury,neurogenic inflammation, pain, and reperfusion injury of the brain canbe conveniently treated with capsules, cachets or tablets eachcontaining 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or500 mg of the active ingredient of the compound of the presentapplication, or a pharmaceutically acceptable salt thereof, administeredonce, twice, or three times daily.

Inflammatory disorders such as psoriatic arthritis, rheumatoidarthritis, ankylosing spondylitis, osteoarthritis, inflammation andcytokine-mediated chronic tissue degeneration can be convenientlytreated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the activeingredient of the compound of the present application, or apharmaceutically acceptable salt thereof, administered once, twice, orthree times daily.

Allergic disorders such as allergic rhinitis, allergic conjunctivitis,and eosinophilic granuloma can be conveniently treated with capsules,cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compoundof the present application, or a pharmaceutically acceptable saltthereof, administered once, twice, or three times daily.

Psychiatric disorders such as depression, memory impairment, andmonopolar depression can be conveniently treated with capsules, cachetsor tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300mg, 400 mg, or 500 mg of the active ingredient of the compound of thepresent application, or a pharmaceutically acceptable salt thereof,administered once, twice, or three times daily.

Neurodegenerative disorders such as Parkinson disease, Alzheimer'sdisease, acute and chronic multiple sclerosis can be convenientlytreated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the activeingredient of the compound of the present application, or apharmaceutically acceptable salt thereof, administered once, twice, orthree times daily.

Dermatological disorders such as psoriasis and other benign or malignantproliferative skin diseases, atopic dermatitis, and urticaria can beconveniently treated with capsules, cachets or tablets each containing 1mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of theactive ingredient of the compound of the present application, or apharmaceutically acceptable salt thereof, administered once, twice, orthree times daily.

Oncological diseases such as cancer, tumor growth and cancerous invasionof normal tissues can be conveniently treated with capsules, cachets ortablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300mg, 400 mg, or 500 mg of the active ingredient of the compound of thepresent application, or a pharmaceutically acceptable salt thereof,administered once, twice, or three times daily.

Metabolic disorders such as diabetes insipidus can be convenientlytreated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the activeingredient of the compound of the present application, or apharmaceutically acceptable salt thereof, administered once, twice, orthree times daily.

Bone disorders such as osteoporosis, cardiovascular disorders such asarterial restenosis, atherosclerosis, reperfusion injury of themyocardium, and other disorders such as chronic glomerulonephritis,vernal conjunctivitis, transplant rejection and graft versus hostdisease, and cachexia can be conveniently treated with capsules, cachetsor tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300mg, 400 mg, or 500 mg of the active ingredient of the compound of thepresent application, or a pharmaceutically acceptable salt thereof,administered once, twice, or three times daily.

For enhancement of cognition (such as for of enhancied memory, learning,retention, recall, awareness and judgement), dosage levels from about0.0001 mg/kg to about 50 mg/kg of body weight per day are useful orabout 0.005 mg to about 2.5 g per patient per day. Alternatively, dosagelevels from about 0.001 mg to 10 mg of the compound per kilogram of bodyweight per day, or alternatively about 0.05 mg to about 500 mg perpatient per day.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.005 mg to about 2.5 g of active agent,compounded with an appropriate and convenient amount of carrier materia.Unit dosage forms will generally contain between from about 0.005 mg toabout 1000 mg of the active ingredient, typically 0.005, 0.01 mg, 0.05mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg,500 mg, 600 mg, 800 mg or 1000 mg, administered once, twice or threetimes a day.

The abbreviations used herein have the following tabulated meanings.Abbreviations not tabulated below have their meanings as commonly usedunless specifically stated otherwise. Ac acetyl AIBN2,2′-azobis(isobutyronitrile) BINAP 1,1′-bi-2-naphthol Bn benzyl CAMPcyclic adenosine-3′,5′-monophosphate DAST (diethylamino)sulfurtrifluoride DEAD diethyl azodicarboxylate DBU1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL diisobutylaluminum hydride DMAP4-(dimethylamino)pyridine DMF N,N-dimethylformamide dppf1,1′-bis(diphenylphosphino)-ferrocene EDCI1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et₃Ntriethylamine GST glutathione transferase HMDS hexamethyldisilazide LDAlithium diisopropylamide m-CPBA metachloroperbenzoic acid MMPPmonoperoxyphthalic acid MPPM monoperoxyphthalic acid, magnesium salt6H₂O Ms methanesulfonyl = mesyl = SO₂Me Ms0 methanesulfonate = mesylateNBS N-bromo succinimide NSAID non-steroidal anti-inflammatory drug o-Tolortho-tolyl OXONE ® 2KHSO₅.KHSO₄.K₂SO₄ PCC pyridinium chlorochromatePd₂(dba)₃ Bis(dibenzylideneacetone) palladium(0) PDC pyridiniumdichromate PDE Phosphodiesterase Ph Phenyl Phe Benzenediyl PMBpara-methoxybenzyl Pye Pyridinediyl r.t. room temperature Rac. RacemicSAM aminosulfonyl or sulfonamide or SO₂NH₂ SEM2-(trimethylsilyl)ethoxymethoxy SPA scintillation proximity assay TBAFtetra-n-butylammonium fluoride Th 2- or 3-thienyl TFA trifluoroaceticacid TFAA trifluoroacetic acid anhydride THF Tetrahydrofuran ThiThiophenediyl TLC thin layer chromatography TMS-CN trimethylsilylcyanide TMSI trimethylsilyl iodide Tz 1H (or 2H)-tetrazol-5-yl XANTPHOS4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H- xanthene C₃H₅ Allyl

ALKYL GROUP ABBREVIATIONS Me= Methyl Et= ethyl n-Pr= normal propyl i-Pr=isopropyl n-Bu= normal butyl i-Bu= isobutyl s-Bu= secondary butyl t-Bu=tertiary butyl c-Pr= cyclopropyl c-Bu= cyclobutyl c-Pen= cyclopentylc-Hex= cyclohexyl

Assays Demonstrating Biological Activity LPS and FMLP-Induced TNF-α andLTB₄ Assays in Human Whole Blood

Whole blood provides a protein and cell-rich milieu appropriate for thestudy of biochemical efficacy of anti-inflammatory compounds such asPDE4-selective inhibitors. Normal non-stimulated human blood does notcontain detectable levels of TNF-α and LTB₄. Upon stimulation with LPS,activated monocytes express and secrete TNF-α up to 8 hours and plasmalevels remain stable for 24 hours. Published studies have shown thatinhibition of TNF-α by increasing intracellular cAMP via PDE4 inhibitionand/or enhanced adenylyl cyclase activity occurs at the transcriptionallevel. LTB₄ synthesis is also sensitive to levels of intracellular cAMPand can be completely inhibited by PDE4-selective inhibitors. As thereis little LTB₄ produced during a 24 hour LPS stimulation of whole blood,an additional LPS stimulation followed by fMLP challenge of human wholeblood is necessary for LTB₄ synthesis by activated neutrophils. Thus, byusing the same blood sample, it is possible to evaluate the potency of acompound on two surrogate markers of PDE4 activity in the whole blood bythe following procedure.

Fresh blood was collected in heparinized tubes by venipuncture fromhealthy human volunteers (male and female). These subjects had noapparent inflammatory conditions and had not taken any NSAIDs for atleast 4 days prior to blood collection. 500 μL aliquots of blood werepre-incubated with either 2 μL of vehicle (DMSO) or 2 μL of testcompound at varying concentrations for 15 minutes at 37° C. This wasfollowed by the addition of either 10 L vehicle (PBS) as blanks or 10 μLLPS (1 μg/mL final concentration, #L-2630 (Sigma Chemical Co., St.Louis, Mo.) from E. coli, serotype 0111:B4; diluted in 0.1% w/v BSA (inPBS)). After 24 hours of incubation at 37° C., another 10 L of PBS(blank) or 10 μL of LPS (1 μg/mL final concentration) was added to bloodand incubated for 30 minutes at 37° C. The blood was then challengedwith either 10 μL of PBS (blank) or 10 μL of fMLP (1 μM finalconcentration, #F-3506 (Sigma); diluted in 1% w/v BSA (in PBS)) for 15minutes at 37° C. The blood samples were centrifuged at 1500×g for 10minutes at 4° C. to obtain plasma. A 50 μL aliquot of plasma was mixedwith 200 μL methanol for protein precipitation and centrifuged as above.The supernatant was assayed for LTB₄ using an enzyme immunoassay kit(#520111 from Cayman Chemical Co., Ann Arbor, Mich.) according to themanufacturer's procedure. TNF-α was assayed in diluted plasma (in PBS)using an ELISA kit (Cistron Biotechnology, Pine Brook, N.J.) accordingto manufacturer's procedure. IC₅₀ values should be less than about 5 μM,advantageously less than about 2.5 μM. The IC₅O values of Examples 1 to155 ranged from 0.005 μM to 36 μM.

Anti-Allergic Activity In Vivo

Compounds of the invention have been tested for effects on anIgE-mediated allergic pulmonary inflammation induced by inhalation ofantigen by sensitized guinea pigs. Guinea pigs were initially sensitizedto ovalbumin under mild cyclophosphamide-induced immunosuppression, byintraperitoneal injection of antigen in combinations with aluminumhydroxide and pertussis vaccine. Booster doses of antigen were given twoand four weeks later. At six weeks, animals were challenged withaerosolized ovalbumin while under cover of an intraperitoneallyadministered anti-histamine agent (mepyramine). After a further 48 h,bronchial alveolar lavages (BAL) were performed and the numbers ofeosinophils and other leukocytes in the BAL fluids were counted. Thelungs were also removed for histological examination for inflammatorydamage. Administration of compounds of the Examples (0.001-10 mg/kg i.p.or p.o.), up to three times during the 48 h following antigen challenge,lead to a significant reduction in the eosinophilia and the accumulationof other inflammatory leukocytes.

Spa Based PDE Activity Assay Protocol

Compounds which inhibit the hydrolysis of cAMP to AMP by the type-IVcAMP-specific phosphodiesterases were screened in a 96-well plate formatas follows:

In a 96 well-plate at 30° C. the test compound was added (dissolved in 2μL DMSO), 1881 μL of substrate buffer containing [2,8-³H]adenosine3′,5′-cyclic phosphate (cAMP, 100 nM to 50 μM), 10 μM MgCl₂, 1 mM EDTA,50 mM Tris, pH 7.5. The reaction was initiated by the addition of humanrecombinant PDE4 (the amount was controlled so that ˜10% product wasformed in 10 min.). The reaction was stopped after 10 min. by theaddition of 1 mg of PDE-SPA beads (Amersham Pharmacia Biotech, Inc.,Piscataway, N.J.). The product AMP generated was quantified on a WallacMicrobeta® 96-well plate counter (EG&G Wallac Co., Gaithersburg, MD).The signal in the absence of enzyme was defined as the background. 100%activity was defined as the signal detected in the presence of enzymeand DMSO with the background subtracted. Percentage of inhibition wascalculated accordingly. IC₅₀ value was approximated with a non-linearregression fit using the standard 4-parameter/multiple binding sitesequation from a ten point titration.

The IC₅₀ values of Examples 1 to 155 were determined with 100 nM cAMPusing the purified GST fusion protein of the human recombinantphosphodiesterase IVa (met-248) produced from a baculovirus/Sf-9expression system. IC₅₀ values should be less than about 1000 nM,advantageously less than about 250 nM, and even more advantageously lessthan about 100 nM. The IC₅₀ values of Examples 1 to 155 ranged from0.086 nM to 160 nM.

The examples that follow are intended as an illustration of certainpreferred embodiments of the invention and no limitation of theinvention is implied.

Unless specifically stated otherwise, the experimental procedures wereperformed under the following conditions. All operations were carriedout at room or ambient temperature—that is, at a temperature in therange of 18-25° C. Evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) witha bath temperature of up to 60° C. The course of reactions was followedby thin layer chromatography (TLC) and reaction times are given forillustration only. Melting points are uncorrected and ‘d’ indicatesdecomposition. The melting points given are those obtained for thematerials prepared as described. Polymorphism may result in isolation ofmaterials with different melting points in some preparations. Thestructure and purity of all final products were assured by at least oneof the following techniques: TLC, mass-spectrometry, nuclear magneticresonance (NMR) spectrometry or microanalytical data. Yields are givenfor illustration only. When given, No data is in the form of delta (δ)values for major diagnostic protons, given in parts per million (ppm)relative to tetramethylsilane (TMS) as internal standard, determined at300 MHz, 400 MHz or 500 MHz using the indicated solvent. Conventionalabbreviations used for signal shape are: s. singlet; d. doublet; t.triplet; m. multiplet; br. broad; etc. In addition, “Ar” signifies anaromatic signal. Chemical symbols have their usual meanings; thefollowing abbreviations have also been used: v (volume), w (weight),b.p. (boiling point), m.p. (melting point), L (liter(s)), mL(milliliters), g (gram(s)), mg (milligrams(s)), mol (moles),mmol(millimoles), eq (equivalent(s)).

METHODS OF SYNTHESIS

Compounds of the present invention can be prepared according to thefollowing general methods. Reactions are typically run under nitrogenatmosphere at ambient temperature if not otherwise mention. Anhydroussolvent such as TB, DMF, Et₂O, DME and Tol are commercial grade.Reagents are commercial grade and were used without any purification.Flash chromatography is run on silica gel (230-400 mesh).

All 8-aryl-quinoline of the type I were prepared (SCHEME 1 and SCHEME2)using a Suzuki coupling to build the biaryl moiety. In a typical Suzukicoupling reaction, all reagents except for the palladium catalyst aremixed in the appropriate solvent. The mixture is then degassed (—O₂) byrefluxing for 15 min under nitrogen atmosphere, then cooling to rt, orby applying two to three vacuum/nitrogen sequences. The palladiumcatalyst is then added and the reaction mixture is stirred at theappropriate temperature until completion as monitored by TLC.

The substituents are the same as in Formula I except where definedotherwise. Compounds of the type I (SCHEME 1) can be prepared in a twostep one-pot manner by generating in-situ the boronate analog of 8-bromoquinoline II followed by a palladium catalyzed coupling with theappropriate biaryl III

In most cases, compounds were prepared by the two procedures describedin SCHEME 2. A Suzuki coupling between the 8-bromo-quinoline II and thebromo-phenyl-boronic acid IV produced to the common intermediate V. Thelatter can be coupled with either an aryl-stannane of type VI or aboronic acid of type VII to generate the desired compound I.Alternatively, the arylbromide V can be converted to the correspondingpinacole boronate VIII by a PdCl₂(dppf)₂ catalyzed coupling reactionwith pinacole diborane. Subsequently, a Suzuki coupling of the boronateVIII with the appropriate heteroaryl bromide IX will generate thedesired compound I

Boronic acid of the type VII can be prepared (SCHEME 3) bylithium-halogen exchange at low temperature in THF or Et₂O on thecorresponding heteroaryl bromide IX followed by the addition of atrialkyl-boronate (B(OR)₃). Hydrolysis, under acidic condition, of theresulting heteroaryl-boronate will generate the desired boronic acidVII. Likewise, lithium-halogen exchange or deprotonation at lowtemperature in THF or Et₂O followed by the addition of atrialkylstannyl-chloride (R₃SnCl) generates the stannane of type VI.

Intermediate of the type X can be generated by a mono lithium-halogenexchange at low temperature in ether followed by addition of variouselectrophils as exemplified in SCHEME 3a. Intermediate of the type XIcan be generated by a selective mono lithium-halogen exchange at the 2position in toluene at low temperature followed by addition of variouselectrophils as exemplified in SCHEME 3a. Intermediate of the type XIIcan be prepared by a selective nucleophilic displacement by using thesodium salt generated in DMF of various alcohols and mercaptans asexemplified in SCHEME 3a.

Intermediate of the type XIV can be generated in two steps by first,lithium-halogen exchange at low temperature in ether followed byaddition of1-trimethylsilanyl-2-(2-trimethylsilanyl-ethyldisulfanyl)-ethane toyield the thio-ether XIII. Secondly, upon addition of TBAF to XIII thethio-phenolate is formed and addition of the electrophile RX willgenerate the desired intermediate XIV. A similar reaction can be achieveon the sulfone XV, which will generate a nucleophilic sulfinate uponaddition of TBAF.

Intermediates such as XVIII are prepared from the steric hindered esterXVII. Deprotonation using lithium iso-propyl-cyclohexyl amine (1 eq.)followed by addition of MeI affords the mono alkylated analog. Repeatingseveral time the same procedure will finally give the desired esterXVIII. The cyclopropyl ester XX can be prepare by a palladium catalyzedcyclopropanation using diazomethane.

All the intermediates used for the preparation of the followingcompounds are commercially available or are prepared according to thelitterature. The quinoline intermediates in Table 1 were prepared usingthe following procedures. TABLE 1 Compound Structure Quinoline 1

Quinoline 2

Quinoline 3

Quinoline 4

Quinoline 1 8-Bromo-6-isopropyl-quinoline

The preparation of Quinoline 1 is described in International PatentPublication WO 94/22852.

Quinoline 2 8-Bromo-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline Step1: 8-Bromo-6-methanesulfonylmethyl-quinoline

To a solution of 6-bromomethyl-8-bromoquinoline (1.0 eq.) described inInternational Patent Publication WO 94/22852 in DMF, was added sodiummethanesulfinate (1.4 eq.). After stirring overnight at rt, the mixturewas quenched with H₂O, stirred for 1 h. The resulting precipitate wasisolated by filtration and washed with Et₂O to afford the titlecompound.

Step 2: Quinoline 2

To a solution of 8-bromo-6-methanesulfonylmethyl-quinoline from Step 1(1 eq.) in THF (0.2M) at 0° C., was added potassium t-butoxide (1.3 eq.)over 30 min. After 0.5 h at 0° C., MeI (1.6 eq.) was added and thereaction mixture was stirred at 0° C. for 2 h. A second portion ofpotassium t-butoxide (1.3 eq.) was added over 30 min, followed by MeI(1.6 eq.). The final mixture was stirred at rt for 2 h. The mixture waspoured in saturated aqueous NH4Cl and extracted with EtOAc (2×). Thecombined organic extracts were washed with brine, dried over MgSO₄,filtered and concentrated. The residue was vigorously stirred in Et₂Oand the title compound was isolated by filtration as a pale yellowsolid.

Quinoline 38-(3-Bromo-phenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

A mixture of Quinoline 2 (1.0 eq.), 3-bromo phenylboronic acid (1.05eq), Na₂CO₃ (2M in H₂O; 3.6 eq.) and Pd(PPh₃)₄ (0.03 eq.) in DME (0.2M)was stirred at 80° C. for 8 h. The resulting mixture was cooled to rtand diluted with water under vigourous stirring. The resultingprecipitate-was filtered and dried. Flash chromatography (Hex:EtOAc;2:3) and stirring in a mixture of Et₂O and CH₂Cl₂ (10:1) yielded thetitle compound as a light yellow solid after filtration.

Quinoline 46-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-quinoline

A mixture of Quinoline 3 (1.0 eq.), pinacole diborane ester (1.4 eq) andKOAc (3.5 eq.) and PdCl₂(dppf)₂ (0.03 eq.) in DMF (0.14M) was stirred at60° C. for 24 h. An extra amount of pinacole diborane (0.3 eq), KOAc(1.05 eq.) and PdCl₂(dppf)₂ (0.01 eq.) were added and the mixture wasstirred at 60° C. for 24 h. The resulting mixture was cooled to rt,diluted with EtOAc:Et₂O (1:1). The organic phase was washed with water(3×), brine, dried over MgSO₄, filtered and concentrated. Flashchromatography (CH₂Cl₂:EtOAc; 9:1) and stirring in Et₂O:EtOAc (10:1)afforded the title compound as a white solid.

EXAMPLE 1 8-Biphenyl-3-yl-6-isopropyl-quinoline

To a solution of Quinoline 1 (1.0 eq.) in Et₂O (0.1M) at −78° C. wasadded dropwise sec-BuLi (1.0 eq.). The mixture was stirred for 15 minthen tri-isopropyl boronate (1.1 eq.) was added. The final mixture waswarm to rt and concentrated. To the residue was added 3-bromo-1,1′biphenyl (1.5 eq.), Na₂CO₃ (2M in H₂O; 3.5 eq.) and Pd(PPh₃)₄ (0.0 Seq.)in Tol:EtOH (1:1, 0.2M). The mixture was stirred at 80° C. for 12 h,cooled to rt, poured in saturated aqueous NH₄Cl and extracted with EtOAc(2×). The combined organic extracts were washed with brine, dried overNa₂SO₄, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1)afforded the title compound as an oil. ¹H NMR (400 MHz, acetone-d₆): δ8.82 (dd, 1H), 8.32 (dd, 1H), 7.99 (t, 1H), 7.81 (m, 2H), 7.75-7.66 (m,4H), 7.55 (t, 1H), 7.5-7.45 (m, 3H), 7.36 (t, 1H), 3.21 (m, 1H), 1.39(d, 6H).

EXAMPLE 21-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-1-phenyl-ethanol

Step1:1-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-ethanone

A mixture of Quinoline 3 (1.0 eq.), (3-acetyl-phenyl)-boronic acid (1.5eq.), Na₂CO₃ (3.0 eq.; 2M in H₂O) and PdCl₂(dppf)₂ (0.05 eq.) inn-propanol (0.2M) was stirred at 80° C. for 2 h. The mixture was cooledto rt, poured in brine and extracted with EtOAc (2×). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated.Flash chromatography (Hex:EtOAc; 9:1 to 1:9 over 20 min) afforded thetitle compound as a yellow solid.

Step 2: EXAMPLE 2

To a solution of1-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-biphenyl-3-yl}-ethanonefrom Step 1 (1.0 eq.) in THF (0.1M) was added CeCl₃ (1.1 eq.). Themixture was put in an ultrasonic bath for 15 min, cooled to −78° C. thenphenyl magnesium bromide was added (5.0 eq.). The final mixture wasstirred for 12 h at −20° C., poured in NaHCO₃ and extracted with EtOAc(2×). The combined organic extracts were washed with brine, dried overNa₂SO₄, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1to 1:9 over 20 min) afforded the title compound as a white solid. ¹H NMR(400 MHz, acetone-d₆): δ 8.91 (dd, 1H), 8.46 (dd, 1H), 8.29 (d, 1H),8.18 (d, 1H), 7.97 (d, 1H), 7.86 (d, 1H), 7.68 (dd, 1H), 7.64 (dd, 1H),7.59-7.50 (m, 5H), 7.48 (d, 1H), 7.39 (t, 1H), 7.27 (t, 2H), 7.16 (t,1H), 4.73 (s, 1H), 2.72 (s, 3H), 1.99 (s, 6H), 1.98 (s, 3H).

EXAMPLE 38-[3-(5—Chloro-thiophen-2-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

A mixture of Quinoline 4 (1.0 eq.), 2-bromo-3-chloro-thiophene (2.0eq.), Na₂CO₃ (3.0 eq.; 2M in H₂O) and PdCl₂(dppf)₂ (0.0 Seq.) in DME(0.2M) was stirred at 80° C. for 12 h. The mixture was cooled to rt andconcentrated. Flash chromatography (Hex:EtOAc; 9:1 to 1:9 over 20 min)afforded the title compound as a yellow solid. ¹H NMR (400 MHz,acetone-d₆): δ 8.93 (dd, 1H), 8.47 (dd, 1H), 8.3 (d, 1H), 8.19 (d, 1H),7.97 (t, 1H), 7.69-7.64 (m, 2H), 7.60-7.52 (m, 2H), 7.35 (d, 1H), 7.07(d, 1H), 2.72 (s, 3H), 2.00 (s, 6H).

EXAMPLE 48-(3-Benzofuran-2-yl-phenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

A mixture of Quinoline 3 (1.0 eq.), 2-benzofuran boronic acid (1.2 eq.),Na₂CO₃ (2.5 eq.; 2M in H₂O) and Pd(PPh₃)₄ (0.05 eq.) in DME (0.1M) wasstirred at 80° C. for 12 h. The mixture was cooled to rt, poured insaturated aqueous NH₄Cl and extracted with EtOAc (2×). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Flash chromatography (Hex:EtOAc; 9:1 to 1:9 in 20 min)afforded the title compound as a yellow solid. ¹H NMR (500 MHz,acetone-d₆): δ 8.93 (dd, 1H), 8.47 (dd, 1H), 8.30 (dd, 2H), 8.21 (s,1H), 7.98 (dd, 1H), 7.75-7.55 (m, 5H), 7.30 (m, 2H), 7.25 (t, 1H), 2.73(s, 3H), 2.01 (s, 6H).

EXAMPLE 5{4-Fluoro-3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-methanol

Step 1: 5-Bromo-2-fluoro-benzylalcohol

To a solution of 5-bromo-2-fluoro-benzaldehyde (1.0 eq.) in MeOH (0.2M)at 0° C. was added portionwise NaBH4 (2.0 eq.). The mixture was stirredat rt for 1 h, poured in HCl (1M) and extracted with EtOAc (2×). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated to afford the title compound as a white solid.

Step 2: 4-Fluoro-3-hydroxymethyl-phenylboronic acid.

To a solution of 5-bromo-2-fluoro-benzylalcohol (1.0 eq.) from Step 1 inTHF (0.1M) at −78° C. was added dropwise n-BuLi (2.2 eq.). The mixturewas stirred at −78° C. for 15 min then tri-isopropylboronate (2.2 eq.)was added. The final mixture was warm slowly to rt, stirred for 1 h andquenched with HCl (1M). After stirring for 1 h, the mixture wasextracted with EtOAc (2×). The combined organic extracts were washedwith water, brine, dried over Na₂SO₄, filtered and concentrated.Stirring in Hex:EtOAc:H₂O (90:9:1) for 12 h afforded the title compoundwhich was isolated by filtration as a white solid.

Step 3: EXAMPLE 5

Prepared according to the procedure described in EXAMPLE 4 but using4-fluoro-3-hydroxymethyl-phenylboronic acid from Step 2 as startingmaterial.

The title compound was obtained as a yellow solid. ¹H NMR (500 MHz,acetone-d₆): δ8.91 (dd, 1H), 8.44 (dd, 1H), 8.28 (d, 1H), 8.20 (d, 1H),7.99 (t, 1H), 7.87 (dd, 1H), 7.70-7.55 (m, 5H), 7.17 (t, 1H), 4.75 (d,2H), 4.38 (t, OH), 2.72 (s, 3H), 1.99 (s, 6H).

EXAMPLE 62-(6-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-2-yl)-propan-2-ol

Step 1: 2-(6-Bromo-pyridin-2-yl)-propan-2-ol

To a suspension of 2,6-dibromopyridine (1.0 eq.) in Et2O (0.2M) at −78°C. was added dropwise n-BuLi (1.05 eq.). The mixture was stirred at −78°C. for 45 min then acetone (1.5 eq.) was added. The final mixture wasstirred for an extra 15 min at −78° C. and quenched with saturatedaqueous NaHCO₃. The mixture was extracted with EtOAc (2×). The combinedorganic extracts were washed with, brine, dried over MgSO₄, filtered andconcentrated to afford the title compound as a white solid which wasused as such.

Step 2: EXAMPLE 6

A mixture of Quinoline 4 (1.0 eq.), 2-(6-bromo-pyridin-2-yl)-propan-2-ol(1.2 eq.), Na₂CO₃ (3.5 eq.; 2M in H₂O), Pd(OAc)₂ (0.05 eq.) and PPh₃(0.1 Seq.) in n-propanol (0.1M) was stirred at 80° C. for 15 min. Themixture was cooled to rt, poured in water and extracted with EtOAc (2×).The combined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated. Flash chromatography (Tol:Ace; 9:1) affordedthe title compound as a white solid. ¹H NMR (500 MHz, acetone-d₆): δ8.95 (dd, 1H), 8.53 (t, 1H), 8.48 (dd, 1H), 8.32 (d, 1H), 8.26 (d, 1H),8.20 (dt, 1H), 7.92-7.81 (m, 3H), 7.65-7.58 (m, 3H), 4.83 (s, OH), 2.76(s, 3H), 2.03 (s, 6H:), 1.58 (s, 6H).

EXAMPLE 76-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methanesulfonyl-pyridin-2-yl)-phenyl]-quinoline

Step 1: 2-Bromo-6-methylsulfanyl-pyridine

To a solution of 2,6-dibromopyridine. (1.0 eq.) in DMSO (0.3M) was addedsodium methylsulfide (1.1 eq.). The mixture was stirred for 2 d at rtthen poured in water. The resulting precipitate was filtered off and thefiltrate was extracted with Et₂O (2×). The combined organic extractswere washed with brine, dried over MgSO₄, filtered and concentrated toafford the title compound as a colorless oil.

Step 2:6-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methylsulfanyl-pyridin-2-yl)-phenyl]-quinoline

Prepared according to the procedure described in EXAMPLE 6, Step 2 butusing 2-bromo-6-methylsulfanyl-pyridine as starting material. The titlecompound was obtained as a light yellow solid.

Step 3: EXAMPLE 7

To a solution of6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methylsulfanyl-pyridin-2-yl)-phenyl]-quinolinefrom Step 2 (1.0 eq.) in THF:MeOH: saturated aqueous NaHCO₃ (2:1:1) wasadded Oxone (2.2 eq.). The mixture was stirred for 12 h at rt, poured inwater and extracted with EtOAc (2×). The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Flashchromatography (Tol:Ace; 4:1) afforded the title compound as a whitesolid. ¹H NMR (500 MHz, acetone-d₆): δ 8.93 (dd, 1H), 8.55 (t, 1H), 8.46(dd, 1H), 8.30-8.20 (m, 5H), 7.99 (dd, 1H), 7.89 (dt, 1H), 7.65 (t, 1H),7.57 (dd, 1H), 3.33 (s, 3H), 2.74 (s, 3H), 2.00 (s, 6H).

EXAMPLE 86-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methanesulfonyl-pyridin-3-yl)-phenyl]-quinoline

Step 1: 3-Bromo-6-methylsulfanyl-pyridine

To a solution of 3,6-dibromopyridine (1.0 eq.) in DMSO (0.3M) was addedsodium methylsulfide (1.1 eq.). The mixture was stirred for 2 d at rtthen poured in water. The resulting precipitate was filtered to affordthe title compound as white solid.

Step 2:6-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methylsulfanyl-pyridin-3-yl)-phenyl]-quinoline

Prepared according to the procedure described in EXAMPLE 6, Step 2 butusing 3-bromo-6-methylsulfanyl-pyridine as starting material. The titlecompound was obtained as a light yellow solid.

Step 3: EXAMPLE 8

Prepared according to the procedure described in EXAMPLE 7, Step 3 butusing6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methylsulfanyl-pyridin-3-yl)-phenyl]-quinolineas starting material. The title compound was obtained as a white solid.¹H NMR (500 MHz, acetone-d₆): δ 9.08 (d, 1H), 8.93 (dd, 1H), 8.45 (dd,1H), 8.41 (dd, 1H), 8.31 (d, 1H), 8.24 (d, 1H), 8.16 (t, 1H), 8.11 (d,1H), 7.86 (dd, 1H), 7.82 (d, 1H), 7.65 (t, 1H), 7.56 (dd, 1H), 3.26 (s,3H), 2.73 (s, 3H), 2.00 (s, 6H).

EXAMPLE 96-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(5-methanesulfonyl-loxy-pyridin-3-yl)-phenyl]-quinoline

Step 1: (5-Methylsulfanyl-pyridin-3-yl)-boronic acid

To a suspension of 3,5-dibromopyridine (1.0 eq.) in Et₂O (0.1M) at −78°C. was added dropwise n-BuLi (1.05 eq.). The mixture was stirred at −78°C. for 15 min then dimethyldisulfide (1.0 eq.) was added. The mixturewas stirred for 15 min and a second portion of n-BuLi (1.0 Seq.) wasadded. After stirring for 1 h at −78° C., tri-iso-propylboronate (1.5eq.) was added. The final mixture was warmed slowly to rt and stirredfor 12 h. An aqueous solution of HCl (1M) was added dropwise until pH=5.The resulting precipitate was filtered to afford the title compound as awhite solid, which was used as such.

Step 2:6-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(5-methylsulfanyl-pyridin-3-yl)-phenyl]-quinoline

Prepared according to the procedure described in EXAMPLE 4 but using(5-methylsulfanyl-pyridin-3-yl)-boronic acid as starting material. Uponcompletion of the reaction (4 h), the title compound was isolated byflash chromatography (EtOAc) as a light yellow solid.

Step 3:6-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(5-methanesulfonyl-pyridin-3-yl)-phenyl]-quinoline

Prepared according to the procedure described in EXAMPLE 7, Step 3, butusing6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(5-methylsulfanyl-pyridin-3-yl)-phenyl]-quinolinefrom step 2 as starting material. Flash chromatography was not requiredto get clean material.

Step 4: EXAMPLE 9

To a solution of6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(5-methanesulfonyl-pyridin-3-yl)-phenyl]-quinoline(1.0 eq.) in CH₂Cl₂ (0.1M) was added m-CPBA (1.3 eq.). The mixture wasstirred at rt for 12 h, quenched with Ca(OH)₂ (0.7 eq) diluted withCH₂Cl₂ and filtered. The filtrate was concentrated and flashchromatography (EtOAc:MeOH; 9:1) afforded the title compound as a whitesolid. ¹H NMR (500 MHz, acetone-d₆): δ 8.95 (dd, 1H), 8.74 (t, 1H), 8.54(t, 1H), 8.48 (dd, 1H), 8.33 (d, 1H), 8.24 (d, 1H), 8.17 (t, 1H), 8.06(t, 1H), 7.87 (t, 1H), 7.69 (t, 1H), 7.60 (dd, 1H), 3.40 (s, 3H), 2.75(s, 3H), 2.02 (s, 6H).

EXAMPLE 108-(4′-Methanesulfonylmethyl-biphenyl-3-yl)₆-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Step 1:{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-methanol

Prepared according to the procedure described in EXAMPLE 4 but using(4-hydroxymethyl-phenyl)-boronic acid as starting material. Flashchromatography (Hex:EtOAc; 1:1) afforded the title compound as a whitesolid.

Step 2:8-(4′-Bromomethyl-biphenyl-3-yl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline.

To a solution of{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-methanolfrom Step 1 (1.0 eq.) in AcOH (0.3M) was added HBr (48%; 9.5 eq.). Themixture was stirred at 80° C. for 12 h, cooled to rt, poured in coldwater containing 10 eq. of NaOH and extracted with EtOAc. The organicextract was washed with saturated aqueous NaHCO₃ (3×), brine, dried overNa₂SO₄, filtered and concentrated to afford the title compound as ayellow solid.

Step 3: EXAMPLE 10

To a solution of8-(4′-Bromomethyl-biphenyl-3-yl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline(1.0 eq.) in DMF (0.1M) was added sodium methanesulfinate (1.3 eq.). Themixture was stirred at rt for 2 h, poured in water and extracted withEtOAc (2×). The combined organic extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated. Flash chromatography (Hex:EA;1:4) and stirring in EtOAc:Hex:Et₂O (1:7:2) afforded the title compoundas a white solid after filtration. ¹H NMR (400 MHz, acetone-d₆): δ 8.96(dd, 1H), 8.49 (dd, 1H), 8.32 (d, 1H), 8.25 (d, 1H), 8.08 (t, 1H),7.81-7.75 (m, 4H), 7.63-7.59 (m, 4H), 4.48 (s, 2H), 2.90 (s, 3H), 2.75(s, 3H), 2.03 (s, 6H).

EXAMPLE 11N-Cyclopropyl-3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-acrylamide

Step 1:3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-carbaldehyde

Prepared according to the procedure described in EXAMPLE 4 but using(3-Formyl-phenyl)-boronic acid as starting material. Flashchromatography (CH₂Cl₂:EtOAc; 9:1) afforded the title compound as awhite solid.

Step 2:3-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-acrylicacid

To a solution of3′-[6-(1-methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-biphenyl-3-carbaldehydefrom Step 1 (1.0 eq.) and (dimethoxy-phosphoryl)-acetic acid methylester (1.1 eq.) in THF (0.1M) was added t-BuOK (1.1 eq.; 1.0M in THF).The final mixture was stirred 3 h at rt, poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Flashchromatography (CH₂Cl₂:EtOAc; 9:1) afforded the corresponding methylester of the title compound as a yellow solid. To a solution of themethyl ester in THF: MeOH (4:1), aqueous NaOH (3.0 eq.) was added. Thefinal mixture was stirred 4 h at rt, neutralized with AcOH, poured insaturated aqueous NH₄Cl and extracted with EtOAc (2×). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated to afford the title compound as a white solid.

Step 3: EXAMPLE 11

A mixture of3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-biphenyl-3-yl}-acrylicacid from Step 2 (1.0 eq.), EDCI (1.3 eq.), DMAP (2.0 eq.) andcyclopropylamine (10.0 eq.) in CH₂Cl₂ was stirred for 12 h at rt. Themixture was poured in saturated aqueous NH₄Cl and extracted with EtOAc(2×). The combined organic extracts were washed with saturated aqueousNaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated. Flashchromatography (EtOAc) afforded the title compound as a white solid. ¹HNMR (500 MHz, acetone-d₆): δ 8.94 (dd, 1H), 8.46 (dd, 1H), 8.30 (d, 1H),8.24 (d, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.76-7.50 (m, 7H), 7.48 (t,1H), 7.39 (d, NH), 6.7 (d, 1H), 2.87 (m, 1H), 2.75 (s, 3H), 2.02 (s,6H), 0.71 (m, 2H), 0.52 (m, 2H).

EXAMPLE 126-(1-Methanesulfonyl-methyl-ethyl)-8-[3-(6-methyl-1-oxy-pyridin-3-yl)-phenyl]-quinoline

Step 1:6-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methyl-pyridin-3-yl)-phenyl]-quinoline

To a solution of 5-Bromo-2-methyl-pyridine (1.0 eq.) in Et₂O (0.2M) at−78° C. was added dropwise n-BuLi (1.1 eq.). The resulting orangesuspension was stirred 15 min at −78° C. then tri-iso-propylboronate(1.8 eq.) was added and the final mixture was warmed to 0° C. andstirred for 1 h. The reaction mixture was quenched with MeOH dilutedwith Tol and concentrated. To the residue in DME (0.2M) was addedQuinoline 3 (0.35 eq.), Na₂CO₃ (3.7 eq.; aqueous 2M) and PdCl₂(dppf)₂(0.1 eq.). The mixture was stirred at 80° C. for 4 h, cooled to rt,poured in water and extracted with EtOAc (2×). The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Flash chromatography (Tol:Ace; 4:1) afforded the titlecompound as a light yellow solid.

Step 2: EXAMPLE 12

Prepared according to the procedure described in EXAMPLE 9, Step 4, butusing6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methyl-pyridin-3-yl)-phenyl]-quinolinefrom Step I as starting material. Flash chromatography (EtOAc:MeOH; 9:1)afforded the title compound as a light yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.96 (dd, 1H), 8.59 (s, 1H), 8.52 (dd, 1H), 8.29 (d, 1H),8.08 (d, 1H), 7.97 (d, 1H), 7.79 (dd, 1H), 7.74 (dd, 1H), 7.67-7.60 (m,3H), 7.57 (d, 1H), 2.82 (s, 3H), 2.41 (s, 3H), 1.95 (s, 6H).

EXAMPLE 136-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(1-oxy-pyridin-4-yl)-phenyl]-quinoline

Step 1:6-(1-Methanesulfonyl-1-methyl-ethyl)-8-(3-pyridin-4-yl-phenyl)-quinoline.

A mixture of Quinoline 3 (1.0 eq.), pyridin-4-yl-boronic acid (1.2 eq.),Na₂CO₃ (2.5 eq.; 2M in H₂O), Pd(PPh₃)₄ (0.05 eq.) in n-propanol (0.1M)was stirred at 80° C. for 4 h. The mixture was cooled to rt, poured inwater and extracted with EtOAc (2×). The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Flashchromatography (CH₂Cl₂:EtOAc; 1:1) afforded the title compound as awhite solid.

Step 2: EXAMPLE 13

Prepared according to the procedure described in EXAMPLE 9, Step 4, butusing6-(1-methanesulfonyl-1-methyl-ethyl)-8-(3-pyridin-4-yl-phenyl)-quinolinefrom Step 1 as starting material. Flash chromatography (EtOAc:MeOH; 4:1)afforded the title compound as a light yellow solid. ¹H NMR (500 MHz,acetone-d₆): δ 8.93 (dd, 1H), 8.52 (dd, 1H), 8.32 (d, 1H), 8.25 (m, 3H),8.12 (s, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 2.75 (s, 3H), 2.05 (s, 6H).

EXAMPLE 146-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(1-oxy-pyridin-3-yl)-phenyl]-quinoline

Step 1:6-(1-Methanesulfonyl-1-methyl-ethyl)-8-(3-pyridin-3-yl-phenyl)-quinoline

Prepared according to the procedure described in EXAMPLE 13, Step 1, butusing pyridin-3-yl-boronic acid as starting material.

Step 2: EXAMPLE 14

Prepared according to the procedure described in EXAMPLE 9, Step 4, butusing6-(1-methanesulfonyl-1-methyl-ethyl)-8-(3-pyridin-3-yl-phenyl)-quinolinefrom Step 1 as starting material. ¹H NMR (500 MHz, acetone-d₆): δ 8.93(dd, 1H), 8.49 (s, 1H), 8.47 (dd, 1H), 8.32 (d, 1H), 8.23 (d, 1H), 8.15(d, 1H), 8.07 (s, 1H), 7.83 (d, 1H), 7.77 (d, 1H), 7.65 (m, 2H), 7.6(dd, 1H), 7.48 (t, 1H), 2.75 (s, 3H), 2.05 (s, 6H).

EXAMPLE 158-{3-[6-(4-Fluoro-phenylmethanesulfonyl)-pyridin-3-yl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Step 1: 5-Bromo-2-(4-fluoro-benzylsulfanyl)-pyridine

To a solution of 2,5-dibromopyridine (1.0 eq.) and(4-fluoro-phenyl)-methanethiol (1.2 eq.) in DMF (0.2M) at 0° C. wasadded portionwise NaH (1.3 eq.). The mixture was stirred for 1 h at rt,poured in water and extracted with Et₂O. The organic extract was washedwith water (2×), brine, dried over MgSO₄, filtered and concentrated.Flash chromatography (Hex:EtOAc; 9:1) afforded the title compound as ayellow solid.

Step 2: 5-Bromo-2-(4-fluoro-phenylmethanesulfonyl)-pyridine

Prepared according to the procedure described in EXAMPLE 7, Step 3, butusing 5-bromo-2-(4-fluoro-benzylsulfanyl)-pyridine as starting material.Flash chromatography (Hex:EtOAc; 4:1) afforded the title compound as awhite solid.

Step 3: EXAMPLE 15

Prepared according to the procedure described in EXAMPLE 6, Step 2, butusing 5-bromo-2-(4-fluoro-phenylmethanesulfonyl)-pyridine as startingmaterial. The reaction mixture was stirred 2 h at 80° C. Flashchromatography (Tol;Ace; 9:1) afforded the title compound as a whitesolid. ¹H NMR (500 MHz, acetone-d₆): δ 9.20 (d, 1H), 8.97 (dd, 1H), 8.49(dd, 1H), 8.37 (dd, 1H), 8.34 (d, 1H), 8.27 (d, 1H), 8.19 (d, 1H), 7.94(d, 1H), 7.89-7.85 (m, 2H), 7.69 (t, 1H), 7.61 (dd, 1H), 7.37-7.35 (m,2H), 7.08 (t, 2H), 4.78 (s, 2H), 2.76 (s, 3H), 2.03 (s, 6H).

EXAMPLE 162-(5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridin-2-yl)-propan-2-ol

Step 1: 2-(5-Bromo-pyridin-2-yl)-propan-2-ol

To a suspension of 2,5-dibromopyridine (1.0 eq.) in Tol (0.1M) at −78°C. was added dropwise n-BuLi (1.07 eq.). The mixture was stirred at −78°C. for 3 h then acetone (1.2 eq.) was added. The final mixture wasstirred for an extra 2 h at −78° C., poured in saturated aqueous NH₄Cland extracted with Tol (2×). The combined organic extracts were driedover Na₂SO₄, filtered and concentrated. Flash chromatography (Hex:EtOAc;4:1) afforded the title compound as a white solid.

Step 2: 2-(5-Bromo-1-oxy-pyridin-2-yl)-propan-2-ol

Prepared according to the procedure described in EXAMPLE 9, Step 4, butusing 2-(5-bromo-pyridin-2-yl)-propan-2-ol as starting material. Flashchromatography (Hex:EtOAc; 1:1) afforded the title compound as a whitesolid.

Step 3: EXAMPLE 16

Prepared according to the procedure described in EXAMPLE 6, Step 2, butusing 2-(5-bromo-1-oxy-pyridin-2-yl)-propan-2-ol as starting material.Flash chromatography (EtOAc) and stirring in Et₂O:EtOAc (9:1) affordedthe title compound as a white solid after filtration. ¹H NMR (500 MHz,acetone-d₆): δ 8.95 (dd, 1H), 8.71 (d, 1H), 8.54 (dd, 1H), 8.30 (d, 1H),8.08 (d, 1H), 8.00 (d, 1H), 7.86-7.81 (m, 2H), 7.78 (d, 1H), 7.73 (d,1H), 7.66-7.62 (m, 2H), 7.03 (s, OH), 2.82 (s, 3H), 1.95 (s, 6H), 1.63(s, 6H).

EXAMPLE 17N-Cyclopropyl-3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-propionaniide

Step 1:3-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-propionicacid methyl ester

To a solution of3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-acrylicacid methyl ester (1.0 eq.) from EXAMPLE 11, Step 2, in Tol (0.1M) atwas added benzenesulfonyl hydrazide (3.8 eq.). The mixture was stirredat 100° C. for 12 h, cooled to rt, poured in saturated aqueous NaHCO₃and extracted with EtOAc (2×). The combined organic extracts were washedwith brine, dried over MgSO₄, filtered and concentrated. Flashchromatography (CH₂Cl₂:EtOAc; 8.5:1.5) afforded the title compound as awhite solid.

Step 2:3-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-propionicacid

To a solution of3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-propionicacid methyl ester (1.0 eq.) from step 1, in TBF:MeOH (2:1; 0.2M) wasadded aqueous LiOH (2M; 4.0 eq.). The mixture was stirred for 12 h atrt, quenched with AcOH (20 eq.), poured in saturated aqueous NH₄OAc andextracted with EtOAc (2×). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated.Crystallization in Hex:CH₂Cl₂ afforded the title compound as a whitesolid.

Step 3: EXAMPLE 17

Prepared according to the procedure described in EXAMPLE 11, Step 3, butusing3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-propionicacid from step 2, as starting material. ¹H NMR (500 MHz, acetone-d₆): δ8.95 (dd, 1H), 8.48 (dd, 1H), 8.32 (d, 1H), 8.23 (d, 1H), 8.02 (s, 1H),7.71 (m, 2H), 7.60 (m, 41), 7.38 (t, 1H), 7.23 (d, 1H), 7.05 (s, NH),2.98 (t, 2H), 2.75 (s, 3H), 2.64 (m, 1H), 2.46 (t, 2H), 2.03 (s, 6H),0.56 (m, 2H), 0.35 (m, 2H).

EXAMPLE 18{33′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-phosphonicacid diethyl ester

Prepared according to the procedure described in EXAMPLE 6, Step 2, butusing (3-bromo-phenyl)-phosphonic acid diethyl ester as startingmaterial. Upon completion of the reaction (1 h) the title compound wasisolated by flash chromatography (EtOAc) as a light yellow solid. ¹H NMR(500 MHz, acetone-d₆): δ 8.94 (dd, 1H), 8.49 (dd, 1H), 8.32 (d, 1H),8.28 (d, 1H), 8.12 (d, 1H), 8.10 (s, 1H), 8.0 (d, 1H), 7.85-7.55 (m,6H), 4.12 (m, 4H), 2.77 (s, 3H), 2.05 (s, 6H), 1.30 (t, 6H).

EXAMPLE 195-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1H-pyridin-2-one

Step 1: 2-Benzyloxy-5-bromo-pyridine

A mixture of 2,5-dibromopyridine (1.0 eq.), benzyl alcohol (1.3 eq.),KOH (2.4 eq.) and DB-18—C-6 (0.0 Seq.) in toluene (0.3M) was refluxedfor 3 h, then stirred overnight at rt. The mixture was concentrated,poured in water and extracted with Tol (2×). The combined organicextracts were dried over MgSO₄, filtered and concentrated.Recrystallization in Hex:Et₂O afforded the title compound as a whitesolid.

Step 2:8-[3-(6-Benzyloxy-pyridin-3-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Prepared according to the procedure described in EXAMPLE 6, Step 2, butusing 2-benzyloxy-5-bromo-pyridine as starting material. Upon completionof the reaction (1 h) the title compound was isolated by flashchromatography (Tol:Ace; 9:1) as a light yellow solid.

Step 3: EXAMPLE 19

To a solution of8-[3-(6-Benzyloxy-pyridin-3-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinolinefrom Step 2 (1.0 eq.) in CH₂Cl₂ (0.2M) was added an equi volume of TFA.The mixture was stirred for 72 h, concentrated, poured in saturatedaqueous NaHCO₃ and extracted with EtOAc (2×). The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Flash chromatography (CH₂Cl₂:MeOH; 95:5) afforded thetitle compound as a light yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.95 (dd, 1H), 8.53 (d, 1H), 8.28 (d, 1H), 8.04 (d, 1H), 7.89 (dd, 1H),7.79 (s, 1H), 7.75 (s, NH), 7.63-7.53 (m, 4H), 6.46 (d, 1H), 2.82 (s,3H), 1.94 (s, 6H).

EXAMPLE 202-(5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridin-3-yl)-propan-2-ol

Step 1: 2-(5-Bromo-pyridin-3-yl)-propan-2-ol

To a solution of 5-bromo-nicotinic acid ethyl ester (1.0 eq.) in Et₂O(0.3M) at −30° C. was added MeMgBr (2.7 eq.; 3M in Et₂O). The mixturewas refluxed for 2 h, poured in 0.5M aqueous NaH₂PO₄ and extracted withEt₂O (2×). The combined organic extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated. Flash chromatography(Hex:Et₂O:CH₂Cl₂; 2:1:2) afforded the title compound as a yellow oil.

Step 2: 2-(5-Bromo-1-oxy-pyridin-3-yl)-propan-2-ol

Prepared according to the procedure described in EXAMPLE 9, Step 4, butusing 2-(5-bromo-pyridin-3-yl)-propan-2-ol as starting material. Flashchromatography (CH₂Cl₂:EtOH; 9:1) afforded the title compound as a whitesolid.

Step 3: EXAMPLE 20

Prepared according to the procedure described in EXAMPLE 6, Step 2, butusing 2-benzyloxy-5-bromo-pyridine as starting material. Upon completionof the reaction (1 h) the title compound was isolated by flashchromatography (EtOAc:MeOH; 8.5:1.5) as a light yellow solid. ¹H NMR(500 MHz, acetone-d₆): δ 8.90 (dd, 1H), 8.42 (dd, 1H), 8.32 (s, 1H),8.28 (s, 1), 8.26 (s, 1H), 8.20 (d, 1H), 8.03 (t, 1H), 7.74 (m, 2H),7.67 (d, 1H), 7.54 (m, 2H), 5.05 (s, OH), 2.72 (s, 3H), 1.98 (s, 6H),1.58 (s, 6H).

EXAMPLE 21N-(3,5-Dichloro-pyridin-4-yl)-3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-acrylamide

Step 1:3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-carbaldehyde

Prepared according to the procedure described in EXAMPLE 4 but using(4-formyl-phenyl)-boronic acid as starting material. Flashchromatography (Hex:EtOAc; 1:1) afforded the title compound as a whitesolid.

Step 2:3-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl)-acrylicacid

Prepared according to the procedure described in EXAMPLE 11, Step 2, butusing3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-carbaldehydefrom Step 1 as starting material. Stirring in Hex:Et₂O (8:2) affordedthe title compound after filtration.

Step 3:3-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-acrylicacid 4-nitro-phenyl ester

Prepared according to the procedure described in EXAMPLE 11, Step 3 butusing3-(3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl)-acrylicacid and 4-nitro-phenol as starting materials. Stirring in Et₂O affordedthe title compound after filtration.

Step 4: EXAMPLE 21

To a solution of 3,5-dichloro-pyridin-4-ylamine (1.5 eq.) in DMF (0.1M)was added t-BuONa (1.5 eq.). The mixture was stirred for 15 min then3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenylyl}-acrylic acid 4-nitro-phenyl ester (1.0 eq.) was added. The finalmixture was stirred for 12 h, poured in saturated aqueous NH₄Cl andextracted with EtOAc (2×). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated. Flashchromatography (Hex:EtOAc; 9:1 to 1:9 in 20 min) afforded the titlecompound as a yellow solid. ¹H NMR (400 MHz, acetone-d₆): δ 9.44 (br s,1H), 8.97 (dd, 1H), 8.64 (s, 2H), 8.50 (dd, 1H), 8.33 (d, 1H), 8.26 (d,1H), 8.11 (t, 1H), 7.87-7.77 (m, 7H), 7.65-7.60 (m, 2H), 7.09 (d, 1H),2.81 (s, 3H), 2.04 (s, 6H).

EXAMPLE 223-Hydroxy-1-13′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-3-methyl-butan-2-one

Step 1:1-(3-Bromo-phenyl)-3-hydroxy-3-methyl-butan-2-one

A mixture of 1,3-dibromobenzene (1.0 eq.),3-hydroxy-3-methyl-butan-2-one (1.0 eq.), Pd₂(dba)₃ (0.02 eq.), xantphos(0.04 eq.) and t-BuONa (1.1 eq.) in THF (0.15M) was stirred at 60° C.for 2h, poured in saturated aqueous NH₄Cl and extracted with EtOAc (2×).The combined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated. Flash chromatography (Hex:EtOAc; 7:3)afforded the title compound as an oil.

Step 2: EXAMPLE 22

Prepared according to the procedure described in EXAMPLE 6, Step 2, butusing 1-(3-bromo-phenyl)-3-hydroxy-3-methyl-butan-2-one from Step 1 asstarting material. Upon completion of the reaction (1 h) the titlecompound was isolated by flash chromatography (EtOAc:MeOH; 1:1 to 3:7)as a light yellow solid. ¹H NMR (500 MHz, acetone-d₆): δ 8.95 (d, 1H),8.49 (d, 1H), 8.32 (d, 1H), 8.23 (d, 1H), 8.03 (s, H), 7.72 (t, 2H),7.62-7.58 (m, 4H), 7.43 (t, 1H), 7.25 (d, 1H), 4.45 (s, 1H), 4.15 (s,2H), 2.75 (s, 3H), 2.03 (s, 6H), 1.38 (s, 6H).

EXAMPLE 23N-Cyclopropyl-5-{3-[(6(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-nicotinamide

Step 1: 5-Bromo-N-cyclopropyl-nicotinamide

Prepared according to the procedure described in EXAMPLE 11 (Step 3) butusing 5-bromo-nicotinic acid as starting material. Flash chromatography(EtOAc) afforded the title compound as a white solid.

Step 2: 5-Bromo-N-cyclopropyl-1-oxy-nicotinamide

Prepared according to the procedure described in EXAMPLE 9 (Step 4) butusing 5-bromo-N-cyclopropyl-nicotinamide from Step 1 as startingmaterial. Flash chromatography (EtOAc:MeOH; 9:1) afforded the titlecompound as a white solid.

Step 3: EXAMPLE 23

Prepared according to the procedure described in EXAMPLE 6 (Step 2) butusing 5-bromo-N-cyclopropyl-1-oxy-nicotinamide from Step 2 as startingmaterial. Upon completion of the reaction (1 h), flash chromatography(EtOAc:MeOH; 4:1) afforded the title compound as a white solid. ¹H NMR(500 MHz, acetone-d₆): δ 8.94 (dd, 1H), 8.58 (s, 1H), 8.53 (s, 1H), 8.47(d, 1H), 8.33 (d, 1H), 8.23 (d, 1H), 8.19 (s, NH), 8.09 (s, 1H), 8.00(s, 1H), 7.78 (dd, 2H), 7.63 (t, 1H), 7.58 (dd, 1H), 2.94 (m, 1H), 2.76(s, 3H), 2.02 (s, 6H), 0.75 (m, 2H), 0.65 (m, 2H).

EXAMPLE 248-{3-[5-(4-Fluoro-phenylmethanesulfonyl)-1-oxy-pyridin-3-yl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Step 1: [5-(2-Trimethylsilanyl-ethylsulfanyl)-pyridin-3-yl]-boronic acid

To a suspension of 3,5-dibromopyridine (1.0 eq.) in Et₂O (0.18M) at −65°C. was added dropwise n-BuLi (1.15 eq.). The mixture was stirred for 30min then1-trimethylsilanyl-2-(2-trimethylsilanyl-ethyldisulfanyl)-ethane (1.15eq.) was added. The resulting light orange solution was stirred at −65°C. for 20 min. Subsequently, a second portion of n-BuLi (1.15 eq.) wasadded. After stirring for 45 min, tri-iso-propylboronate (1.15 eq.) wasadded. The final mixture was warmed slowly and stirred for 12h at rt,quenched with aqueous HCl (1M) to pH=5, stirred for 30 min, extractedwith Et₂O (2×). The combined organic extracts were poured in aqueousNaOH (1N). The aqueous phase was washed with Et₂O (2×), neutralized topH=5 using HCl (1N) and extracted with Et₂O (2×). The combined organicextracts were washed with brine, dried over MgSO₄, filtered andconcentrated to afford the title compound as a white solid.

Step 2:6-(1-Methanesulfonyl-1-methyl-ethyl)-8-{3-[5-(2-trimethylsilanyl-ethylsulfanyl)-pyridin-3-yl]-phenyl}-quinoline

A mixture of Quinoline 3 (1.0 eq.),[5-(2-trimethylsilanyl-ethylsulfanyl)-pyridin-3-yl]-boronic acid (1.2eq.), Na₂CO₃ (2.5 eq.; 2M in H₂O) and PdCl₂(dppf)₂ (0.06 eq.) in DME(0.2 M) was stirred at 80° C. for 2.5h. The mixture was cooled to roomtemperature, poured in water and extracted with EtOAc (2×). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Flash chromatography (Hex:EtOAc; 3:7) and stirring inHex:Et₂O (1:1) afforded the title compound as a white solid afterfiltration.

Step 3:6-(1-Methanesulfonyl-1-methyl-ethyl)-8-{3-[5-(2-trimethylsilanyl-ethanesulfonyl)-pyridin-3-yl]-phenylI quinoline

Prepared according to the procedure described in EXAMPLE 7 (Step 3) butusing6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[5-(2-trimethylsilanyl-ethylsulfanyl)-pyridin-3-yl]-phenyl}-quinolinefrom Step 2 as starting material. Upon completion of the reaction (4h)and work-up, the title compound (white solid) was isolated and usedwithout any purification.

Step 4:6-(1-Methanesulfonyl-1-methyl-ethyl)-8-(3-[1-oxy-5-(2-trimethylsilanyl-ethanesulfonyl)-pyridin-3-yl]-phenyl}-quinoline

Prepared according to the procedure described in EXAMPLE 9 (Step 4) butusing6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[5-(2-trimethylsilanyl-ethanesulfonyl)-pyridin-3-yl]-phenyl}-quinolinefrom step 3 as starting material. Flash chromatography (EtOAc:EtOH;95:5) and stirring in Et₂O afforded the title compound as a white solidafter filtration.

Step 5: EXAMPLE 24

To a solution of6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[1-oxy-5-(2-trimethylsilanyl-ethanesulfonyl)-pyridin-3-yl]-phenyl}-quinolinefrom Step 4 (1.0 eq.) in DMF (0.2M) was added tetramethyl-ammoniumfluoride (2.4 eq.). The mixture was stirred for 1 h then 4-fluorobenzylbromide (1.3 eq.) was added. The final mixture was stirred for 1 h,poured in water and extracted with EtOAc (2×). The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Flash chromatography (EtOAc:EtOH; 95:5) afforded the titlecompound as a white solid. ¹H NMR (500 MHz, acetone-d₆): δ 8.97 (d, 1H),8.73 (s, 1H), 8.51 (d, 2H), 8.35 (d, 1H), 8.30 (s, 1H), 8.25 (d, 1H),8.07 (s, 1H), 7.88 (d, 1H), 7.76 (m, 1H), 7.69 (t, 1H), 7.63 (dd, 1H),7.45 (dd, 2H), 7.12 (t, 2H), 4.84 (s, 2H), 2.76 (s, 3H), 2.03 (s, 6H).

EXAMPLE 255-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridine-2-carboxylicacid cyclopropylamide

Step 1: 5-Bromo-pyridine-2-carboxylic acid cyclopropylamide

To a solution of 5-bromo-pyridine-2-carboxylic acid methyl ester (1.0eq.) (see Synth. Commun., 1997, 27, 515) in THF:MeOH (2:1; 0.2M) wasadded aqueous LiOH (1M; 3.0 eq.). The mixture was stirred for 12h,concentrated and dried under vacuum. The residue was diluted in CH₂Cl₂(0.2M), oxalyl chloride (8.0 eq.) was added and the mixture was stirredfor 3h, concentrated, dried under vacuum and diluted in CH₂Cl₂ (0.2M).Cyclopropylamine (10 eq.) was added and the mixture was stirred for 2h,poured in saturated aqueous NaHCO₃ and extracted with EtOAc (2×). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated. Flash chromatography (CH₂Cl₂:EtOAc; 9:1)afforded the title compound as a yellow solid.

Step 2: 5-Bromo-1-oxy-pyridine-2-carboxylic acid cyclopropylamide

Prepared according to the procedure described in EXAMPLE 9 (Step 4) butusing 5-bromo-pyridine-2-carboxylic acid cyclopropylamide from Step 1 asstarting material. Flash chromatography (CH₂Cl₂:EtOAc; 9:1) afforded thetitle compound as a white solid.

Step 3: EXAMPLE 25

Prepared according to the procedure described in EXAMPLE 6 (Step 2) butusing 5-bromo-1-oxy-pyridine-2-carboxylic acid cyclopropylamide fromStep 2 as starting material. Flash chromatography (EtOAc) afforded thetitle compound as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 11.18 (d,NH), 8.94 (dd, 1H), 8.49 (d, 1H), 8.41 (d, 1H), 8.24 (d, 1H), 8.06 (s,1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.74 (d, 1H), 7.68 (dd, 1H), 7.60 (m,2H), 7.45 (m, 1H), 2.96 (m, 1H), 2.61 (s, 3H), 1.97 (s, 6H), 0.83 (m,2H), 0.64 (m, 2H).

EXAMPLE 266(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methoxmethyl-1-oxy-pyridin-3-yl)-phenyl]-quinoline

Step 1: 5-Bromo-pyridine-2-carbaldehyde

To a solution of 2,5-dibromopyridine (1.0 eq.) in Tol (O. 1M) at −78° C.was added n-BuLi (1.0Seq.). The mixture was stirred for 2h at −78° C.then DMF (3.0 eq.) was added. The final mixture was stirred for 12h at−78° C., quenched using saturated aqueous NH₄Cl and extracted with Et₂O(2×). The combined organic extracts were washed with brine, dried overMgSO₄, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1)afforded the title compound as an oil.

Step 2: (5-Bromo-pyridin-2-yl)-methanol

To a solution of 5-bromo-pyridine-2-carbaldehyde (1.0 eq.) in THF:EtOH(1:1; 0.2M) at −78° C. was added NaBH₄ (4.0 eq.). The mixture wasstirred for 2h at −78° C., quenched with excess AcOH, poured in aqueousHCl (1M), stirred for 15 min, neutralized to pH=7 with NaOH (1M) andextracted with EtOAc (2×). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated to afford thetitle compound as an oil.

Step 3: (5-Bromo-1-oxy-pyridin-2-yl)-methanol

To a solution of (5-bromo-pyridin-2-yl)-methanol (1.0 eq.) in CH₂Cl₂(0.2M) was added peracetic acid (3.0 eq.). The mixture was stirred for12 h, diluted with CH₂Cl₂ and neutralized with aqueous NaOH (1M) topH=7. The organic phase was decanted, dried over Na₂SO₄ and uponconcentration the title compound crystallized as a white solid and wasisolated by filtration.

Step 4: 5-Bromo-2-methoxymethyl-pyridine 1-oxide

To a solution of (5-bromo-1-oxy-pyridin-2-yl)methanol (1.0 eq.) inTHF:DMF (1:1; 0.2M) was added t-BuOK (1.0M in THF; 1.1 eq.). The mixturewas stirred for 1 h, cooled to −78° C. then MeI (1.1 eq.) was added. Thefinal mixture was warmed to rt, poured in saturated aqueous NH₄Cl andextracted with EtOAc (2×). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated to afforded amixture of the title compound and the starting material (20%) which wasused as such.

Step 5: EXAMPLE 26

A mixture of Quinoline 4 (1.2 eq.), 5-bromo-2-methoxymethyl-pyridine1-oxide (1.0 eq.), PdCl₂(dppf)₂ (0.0 Seq.) and aqueous Na₂CO₃ (2M; 2.5eq.) in n-propanol (0.2M) was stirred at 80° C. for 4 h. The mixture wascooled, poured in brine and extracted with EtOAc (2×). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated.Flash chromatography (EtOAc:MeOH; 9:1) afforded the title compound as alight yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.95 (dd, 1H), 8.72 (s,1H), 8.54 (dd, 1H), 8.30 (d, 1H), 8.08 (d, 1H), 7.98 (s, 1H), 7.79 (t,1H), 7.77 (d, 1H), 7.75 (s, 1H), 7.66-7.62 (m, 2H), 7.56 (d, 1H), 4.62(s, 2H), 3.48 (s, 3H), 2.51 (s, 3H), 1.95 (s, 6H).

EXAMPLE 272-(5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-3-methyl1-oxy-pyridin-2-yl)-propan-2-ol

Step 1: 2,5-Dibromo-3-methyl-pyridine

5-Bromo-3-methyl-pyridin-2-ylamine (1.0 eq.) was added portionwise toaqueous HBr (48%; 1.0M). The mixture was stirred 1 h at rt then cooledto −20° C. Bromine (2.8 eq.) was added dropwise followed by a aqueoussolution of NaNO₂ (1.0M; 2.7 eq.). The final mixture was warmed to rtand stirred for 2 h. The mixture was cooled back to −20° C. then aqueousNaOH (1.0M; 3.0 eq.) was added dropwise over 1 h. The final mixture waswarmed to rt and extracted with Et₂O (2×). The combined organic extractswere washed with brine, dried over MgSO₄, filtered and concentrated toafford the title compound as a yellow solid.

Step 2: 2-(5-Bromo-3-methyl-pyridin-2-yl)-propan-2-ol

Prepared according to the procedure described in EXAMPLE 16 (Step 1) butusing 2,5-dibromo-3-methyl-pyridine from Step 1 as starting material.Flash chromatography (Hex:EtOAc; 9:1) afforded the title compound as awhite solid.

Step 3: 2-(5-Bromo-3-methyl-1-oxy-pyridin-2-yl)-propan-2-ol

Prepared according to the procedure described in EXAMPEL 9 (Step 4) butusing 2-(5-bromo-3-methyl-pyridin-2-yl)-propan-2-ol from Step 2 asstarting material. Flash chromatography (Hex:EtOAc; 1:1) afforded thetitle compound as a white solid.

Step 4: EXAMPLE 27

Prepared according to the procedure described in EXAMPLE 6 (Step 2) butusing (5-bromo-3-methyl-1-oxy-pyridin-2-yl)-propan-2-ol from Step 3 asstarting material. Flash chromatography (EtOAc) afforded the titlecompound as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 9.53 (s, OH), 9.00(dd, 1H), 8.49 (d, H), 8.29 (dd, 1H), 8.10 (d, 2H), 7.90 (s, 1H), 7.78(d, 1H), 7.64 (m, 2H), 7.52 (dd, 1H), 7.46 (d, 1H), 2.67 (s, 3H), 2.60(s, 3H), 2.04 (s, 6H), 1.80 (s, 6H).

EXAMPLE 281,1-Difluoro-1-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-ylsulfanyl)-propan-2-ol

Step 1:Difluoro-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-25phenyl}-pyridin-3-ylsulfanyl)-acetic acid ethyl ester

Prepared according to the procedure described in EXAMPLE 24 (Step 5) butusing6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[5-(2-trimethylsilanyl-ethylsulfanyl)-pyridin-3-yl]-phenyl}-quinolinefrom EXAMPLE 24 (Step 2) and bromo-difluoro-acetic acid ethyl ester asstarting materials. Flash chromatography (Hex:EtOAc; 1:4) and stirringin Hex:Et₂O afforded the title compound as a white solid afterfiltration.

Step 2: EXAMPLE 28

To a solution ofdifluoro-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-ylsulfanyl)-aceticacid ethyl ester from Step 1 (1.0 eq.) in CH₂Cl₂ (0.2M) at −78° C. wasadded MeMgBr (3.0 eq.; 3.0M in Et₂O). The mixture was warmed to rt,stirred for 12 h, poured in saturated aqueous NH₄Cl and extracted withEtOAc (2×). The combined organic extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was dissolved inEtOH (0.2M) then NaBH₄ (3.0 eq.) was added. The mixture was stirred for2 h, poured in saturated aqueous NH₄Cl and extracted with EtOAc (2×).The combined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated. Flash chromatography (Hex:EtOAc; 1:9)afforded the title compound as a white solid. ¹H NMR (400 MHz,acetone-d₆): δ 9.04 (d, 1H), 8.97 (dd, 1H), 8.75 (d, 1H), 8.50 (dd, 1H),8.35-8.34 (m, 2H), 8.26 (d, 1H), 8.13 (s, 1H), 7.85 (dt, 1H), 7.82 (dt,1H), 7.68 (t, 1H), 7.61 (dd, 1H), 5.15 (d, 1H), 4.20 (m, 1H), 2.76 (s,3H), 2.03 (s, 6H), 1.37 (d, 3H).

EXAMPLE 296-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(1-oxy-quinolin-3-yl)-phenyl]-quinoline

Step 1: 3-Bromo-quinoline 1-oxide

To a solution of 3-bromo-quinoline (1.0 eq.) in CH₂Cl₂ (0.2M) was addedperacetic acid (2.0 eq.). The mixture was stirred for 12 h, poured insaturated aqueous NaHCO₃ and extracted with EtOAc (2×). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Crystallization from CH₂Cl₂:Hex afforded the titlecompound as a white solid.

Step 2: EXAMPLE 29

Prepared according to the procedure described in EXAMPLE 6 (Step 2) butusing 3-bromo-quinoline 1-oxide as starting material. Flashchromatography (EtOAc:MeOH; 95:5) afforded the title compound as a whitesolid. ¹H NMR (500 MHz, CDCl₃): δ 8.99 (d, 1H), 8.93 (s, 1H), 8.75 (d,1H), 8.29 (dd, 1H), 8.12 (s, 2H), 8.03 (s, 1H), 7.99 (s, 1H, 7.92 (d,1H), 7.75 (m, 3H), 7.67 (m, 2H), 7.51 (dd, 1H), 2.66 (s, 3H), 2.03 (s,6H).

EXAMPLE 301-Isopropyl-3-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridin-2-yl)-urea

Step 1:1-(5-Bromo-pyridin-2-yl)-3-isopropyl-urea

To a solution of 2-amino-5-bromo-pyridine (1.05 eq.) in TBF (0.2M) wasadded DBU (1.0 eq.) followed by iso-propyl-isocyanate (1.0 eq.). Themixture was stirred for 12 h, diluted with CH₂Cl₂, washed with brine,dried over MgSO₄, filtered and concentrated. Crystallization fromacetone afforded the title compound as a white solid.

Step 2: 1-(5-Bromo-1-oxy-pyridin-2-yl)-3-isopropyl-urea

Prepared according to the procedure described in EXAMPLE 29 (Step 1) butusing 1-(5-bromo-pyridin-2-yl)-3-isopropyl-urea from Step 1 as startingmaterial. Crystallization from acetone afforded the title compound as awhite solid.

Step 3: EXAMPLE 30

Prepared according to the procedure described in EXAMPLE 6 (Step 2) butusing 1-(5-bromo-1-oxy-pyridin-2-yl)-3-isopropyl-urea from Step 2 asstarting material. Flash chromatography (EtOAc:MeOH; 9:1) and stirringin acetone afforded the title compound as a white solid afterfiltration. ¹H NMR (500 MHz, CDCl₃): δ 10.05 (s, NH), 8.98 (d, 1H), 8.59(d, 1H), 8.41 (s, 1H), 8.29 (d, 1H), 8.09 (d, 2H), 7.88 (s, 1H), 7.70(m, 3H), 7.55 (m, 3H), 3.96 (m, 1H), 2.65 (s, 3H), 2.01 (s, 6H), 1.20(s, 6H).

EXAMPLE 316-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-quinoline

Step 1: 3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzoicacid methyl ester

To a solution of3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzaldehyde (1.0eq.) (see WO-0146151) in CH₂Cl₂:MeOH (1:1; 0.1M) was added NaCN (1.8eq.), MnO₂ (8.0 eq.) and AcOH (0.05 eq.). The mixture was stirred for 12h, filtered on celite, and concentrated. Flash chromatography(Hex:EtOAc; 1:1) afforded the title compound as a white solid.

Step 2: 3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzoicacid

To a solution of3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzoic acidmethyl ester from Step 1 (1.0 eq.) in THF (0.2M) was added aqueous LiOH(1.0M; 3.0 eq.). The mixture was stirred for 5 h at 60° C., neutralizedto pH=5 using aqueous HCl (1M) and extracted with CH₂Cl₂ (4×). Thecombined organic extracts were dried over MgSO₄, filtered andconcentrated. Stirring in Hex:Et₂O (1:1) afforded the title compoundafter filtration.

Step 3: EXAMPLE 31

To a solutionof-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzoic acidfrom Step 2 (1.0 eq.) in DMF (0.1M) was added CDI (2.0 eq.) andN-hydroxy-acetamidine (2.0 eq.). The mixture was stirred for 1 h at rtthen 12 h at 120° C. The mixture was cooled, poured in water andextracted with EtOAc. The organic extract was washed with water (2×),brine, dried over Na₂SO₄, filtered and concentrated. Flashchromatography (Hex:EtOAc; 9:1 to 1:9 in 20 min) afforded the titlecompound as a white solid. ¹H NMR (500 MHz, acetone-d₆): δ 8.91 (dd,1H), 8.52 (m, 3H), 8.38 (d, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 7.78 (t,1H), 7.64 (dd, 1H), 2.77 (s, 3H), 2.43 (s, 3H), 2.05 (s, 6H).

EXAMPLE 328-(3-{5-[Difluoro-(3-methyl-[1,2,4]oxadiazol-5-yl)-methylsulfanyl]-pyridin-3-yl}-phenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Step 1:Difluoro-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-ylsulfanyl)-aceticacid

Prepared according to the procedure described in EXAMPLE 31 (Step 2) butusingdifluoro-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-ylsulfanyl)-aceticacid ethyl ester from EXAMPLE 28 (Step 1) as starting material.

Step 2: EXAMPLE 32

Prepared according to the procedure described in EXAMPLE 31 (Step 3) butusingdifluoro-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-ylsulfanyl)-aceticacid from Step 1 as starting material. Flash chromatography (Hex:AcOEt;1:4) afforded the title compound as a white solid. ¹H NMR (500 MHz,acetone-d₆): δ 9.07 (d, 1H), 8.97 (dd, 1H), 8.76 (d, 1H), 8.51 (dd, 1H),8.37 (t, 1H), 8.35 (d, 1H), 8.26 (d, 1H), 8.17 (s, 1H), 7.85 (t, 2H),7.70 (t, 1H), 7.62 (dd, 1H), 2.78 (s, 3H), 2.28 (s, 3H), 2.05 (s, 6H).

EXAMPLE 33N-Cyclopropyl-3-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-yl)-acrylamide

Step 1: 5-Bromo-pyridine-3-carbaldehyde

To a solution of 3,5-dibromopyridine (1.0 eq.) in Et₂O (0.1M) at −78° C.was added n-BuLi (1.05 eq.). The mixture was stirred for 30 min at −78°C. then DMF (3.0 eq.) was added. The final mixture was warmed to rt,stirred for 3 h, quenched using saturated aqueous NH₄Cl and extractedwith EtOAc (2×). The combined organic extracts were washed with brine,dried over MgSO₄, filtered and concentrated. Flash chromatography(Hex:EtOAc; 4:1) afforded the title compound as an oil.

Step 2: 3-(5-Bromo-pyridin-3-yl)-acrylic acid

Prepared according to the procedure described in Example 11 (Step 2) butusing 5-bromo-pyridine-3-carbaldehyde from Step 1 as starting material.

Step 3: 3-(5-Bromo-pyridin-3-yl)-N-cyclopropyl-acrylamide

Prepared according to the procedure described in Example 11 (Step 3) butusing 3-(5-bromo-pyridin-3-yl)-acrylic acid from Step 2 as startingmaterial. Crystallization in CH₂Cl₂ afforded the title compound.

Step 4: EXAMPLE 33

Prepared according to the procedure described in EXAMPLE 6 (Step 2) butusing 3-(5-bromo-pyridin-3-yl)-N-cyclopropyl-acrylamide from Step 3 asstarting material. Flash chromatography (EtOAc:EtOH; 9:1) afforded thetitle compound as a white solid. ¹H NMR (500 MHz, acetone-d₆): δ 8.98(dd, 1H), 8.80 (d, 1H), 8.60 (d, 1H), 8.33 (dd, 1H), 8.07 (d, 2H), 8.01(s, 1H), 7.89 (s, 1H), 7.73 (d, 1H), 7.60 (m, 3H), 7.45 (dd, 1H), 6.58(d, 1H), 6.55 (s, NH), 2.80 (m, 1H), 2.65 (s, 3H), 1.98 (s, 6H), 0.75(m, 2H), 0.55 (m, 2H).

EXAMPLE 34N-Cyclopropyl-2-(5-{3-[6-(1-methanesulfonyl-1-methylethyl)-quinolin-8-yl]-phenyl}-pyridin-3-yl)-acetamide

Step 1: 2-(5-Bromo-pyridin-3-yl)-N-cyclopropyl-acetamide

Prepared according to the procedure described in EXAMPLE 11 (Step 3) butusing (5-bromo-pyridin-3-yl)-acetic acid as starting material.Crystallization in CH₂Cl₂ afforded the title compound.

Step 2: EXAMPLE 34

Prepared according to the procedure described in EXAMPLE 6 (Step 2) butusing 2-(5-bromo-pyridin-3-yl)-N-cyclopropyl-acetamide from Step 1 asstarting material. Flash chromatography (EtOAc:EtOH; 9:1) afforded thetitle compound as a white solid. ¹H NMR (500 MHz, acetone-d₆): δ 8.92(dd, 1H), 8.79 (d, 1H), 8.47 (s, 1H), 8.45 (d, 1H), 8.30 (d, 1H), 8.21(d, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.75 (d, 1H), 7.72 (d, 1H), 7.62(t, 1H), 7.57 (dd, 1H), 7.41 (br s, NH), 3.54 (s, 2H), 2.72 (s, 3H),2.68 (m, 1H), 2.00 (s, 6H), 0.61 (m, 2H), 0.40 (m, 2H).

EXAMPLE 35(5-{3-[6-(1-Methanesulfonyl-1-methylethyl)quinolin-8-yl]-phenyl}pyridin-2yl)-(4-methoxy-phenyl)-methanone

Step 1: (5-Bromo-pyridin-2-yl)-(4-methoxy-phenyl)-methanol

To a solution of 2,5-dibromopyridine (1.0 eq.) in Tol (0.1M) at −78° C.was added n-BuUi (1.05 eq.). The mixture was stirred for 2 h at −78° C.then 4-methoxy-benzaldehyde (1.1 eq.) was added. The final mixture waswarmed 0° C., poured in saturated aqueous NH₄Cl and extracted with Et₂O(2×). The combined organic extracts were washed with brine, dried overMgSO₄, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1to 3:2) and stirring in Hex:Et₂O afforded the title compound as a whitesolid after filtration.

Step 2: (5-Bromo-pyridin-2-yl)-(4-methoxy-phenyl)-methanone

To a solution of (5-bromo-pyridin-2-yl)-(4-methoxy-phenyl)-methanol (1.0eq.) in EtOAc (0.2M) was added MnO₂ (3.0 eq.). The mixture was stirredfor 1 h, filtered on celite and concentrated to afford the titlecompound as a white solid.

Step 3: EXAMPLE 35

Prepared according to the procedure described in EXAMPLE 6 (Step 2) butusing (5-bromo-pyridin-2-yl)-(4-methoxy-phenyl)-methanone from Step 2 asstarting material. Flash chromatography (Hex:EtOAc; 9:1 to 1:4) affordedthe title compound as a foam. ¹H NMR (500 MHz, acetone-d₆): δ 9.08 (d,1H), 8.96 (dd, 1H), 8.48 (dd, 1H), 8.36 (dd, 1H), 8.32 (d, 1H),8.26-8.19 (m, 4H), 8.09 (s, 1H), 7.86 (t, 2H), 7.68 (t, 1H), 7.60 (dd,1H), 7.06 (d, 2H), 3.9 (s, 3H), 2.74 (s, 3H), 2.01 (s, 6H).

EXAMPLE 368-[3-(4—Chloro-1-oxy-pyridin-3-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Step 1: 4—Chloro-3-tributylstannanyl-pyridine

To a solution of LDA (1.2 eq.) in THF (0.2M) at −78° C. was added4-chloro-pyridine (1.0 eq.). The mixture was stirred for 1.5 h at −78°C. then Bu₃SnCl (1.5 eq.) was added. The final mixture was slowly warmedto rt, poured in saturated aqueous NH₄Cl and extracted with EtOAc (2×).The combined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated. Flash chromatography (Hex:EtOAc; 95:5)afforded the title compound as an oil.

Step 2:8-[3-(4—Chloro-pyridin-3-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

A mixture of Quinoline 3 (1.0 eq.),4-chloro-3-tributylstannanyl-pyridine (2.0 eq.), PdCl₂(dppf)₂ (0.05eq.), CuI (0.05 eq.) in dioxane (0.1M) was refluxed for 12 h, cooled tort and concentrated. Flash chromatography (CH₂Cl₂:MeOH; 99:1) affordedthe title compound as a beige foam.

Step 3: EXAMPLE 36

Prepared according to the procedure described in EXAMPLE 9 (Step 4) butusing8-[3-(4-chloro-pyridin-3-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinolinefrom Step 2 as starting material. Flash chromatography (CH₂Cl₂:MeOH;95:5) afforded the title compound as a white solid. ¹H NMR (500 MHz,acetone-d₆): δ 8.96 (dd, 1H), 8.49 (d, 1H), 8.33 (dd, 2H), 8.26 (d, 1H),8.19 (dd, 1H), 7.96 (s, 1H), 7.93 (d, 1H), 7.67 (t, 1H), 7.62 (m, 1H),2.76 (s, 3H), 2.05 (s, 6H).

EXAMPLE 378-[3-(3H-Imidazo[4,5-b]pyridin-6-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Step 1:6-Bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine

To a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (1.0 eq.) (see J. Am.Chem. Soc. 1957, 6421.) in DMF (0.2M) was added NaH (1.4 eq.). Themixture was stirred for 30 min then SEM-Cl (2.0 eq.) was added. Thefinal mixture was stirred for 2 h, poured in saturated aqueous NH₄Cl andextracted with EtOAc (2×). The combined organic extracts were washedwith water (3×), brine, dried over Na2SO₄, filtered and concentrated.Flash chromatography (Hex:EtOAc; 7:3) afforded the title compound as afoam.

Step 2:6-(1-Methanesulfonyl-1-methyl-ethyl)-8-{3-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-phenyl}quinoline

Prepared according to the procedure described in EXAMPLE 6 (Step 2) butusing6-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridinefrom Step 1 as starting material. Flash chromatography (Hex:EtOAc; 2:1to 1:1) afforded the title compound as a foam.

Step 3: EXAMPLE 37

A mixture of6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-phenyl}-quinolinefrom Step 2 (1.0 eq.), TBAF (2.0 eq.) and ethylene diamine (1.5 eq.) inDMF (0.2M) was stirred at 80° C. for 3 h. The mixture was cooled,diluted with water, filtered. The resulting solid was stirred in acetoneto afford the title compound after filtration. ¹H NMR (500 MHz,DMSO-d₆): δ 8.94 (dd, 1H), 8.72 (s, 1H), 8.52 (dd, 1H), 8.47 (s, 1H),8.30-8.25 (m, 2H), 8.08 (d, 1H), 7.98 (s, 1H), 7.79 (d, 1H), 7.68 (d,1H), 7.63-7.60 (m, 2H), 2.81 (s, 3H), 1.93 (s, 6H).

EXAMPLE 38N-Cyclopropyl-3-(3-{5-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-1-oxy-pyridin-3-yl}-phenyl)-acrylamide

Step 1:8-(5-Bromo-pyridin-3-yl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

To a solution of 3,5-dibromo-pyridine (1.2 eq.) in Et₂O (0.1M) at −78°C. was added dropwise sec-BuLi (1.05 eq.). The mixture was stirred for30 min then tri-isopropyl boronate (1.5 eq.) was added. The finalmixture was warm to rt, diluted with iso-propanol and concentrated. Tothe residue in n-propanol (0.1M) was added Quinoline 3 (1.0 eq.), Na₂CO₃(2M in H₂O; 3.5 eq.), Pd(OAc)₂ (0.05 eq.) and PPh₃ (0.15 eq). Themixture was stirred at 80° C. for 2 h, cooled to rt, poured in saturatedaqueous NH₄Cl and extracted with EtOAc (2×). The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Flash chromatography (CH₂Cl₂:EtOAc; 1:1 to 0:1) affordedthe title compound as a white solid.

Step 2:8-(5-Bromo-1-oxy-pyridin-3-yl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Prepared according to the procedure described in EXAMPLE 9 (Step 4) butusing8-(5-bromo-pyridin-3-yl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinolinefrom Step 1 as starting material. Flash chromatography (EtOAc:EtOH; 4:1)afforded the title compound as a white solid.

Step 3:3-(3-{5-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-1-oxy-pyridin-3-yl}-phenyl)-acrylicacid

Prepared according to the procedure described in EXAMPLE 6 (Step 2) butusing 3-(2-carboxy-vinyl)phenyl boronic acid and8-(5-Bromo-1-oxy-pyridin-3-yl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinolinefrom Step 2 as starting materials. Flash chromatography (EtOAc:EtOH;9:1) and stirring in CH₂Cl₂:Hex afforded the title compound as a whitesolid after filtration.

Step 4: EXAMPLE 38

Prepared according to the procedure described in EXAMPLE 11 (Step 3) butusing-(3-{5-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-1-oxy-pyridin-3-yl}-phenyl)-acrylicacid from Step 3 as starting material. Flash chromatography (EtOAc:EtOH;4:1) afforded the title compound as a white solid. ¹H NMR (500 MHz,CDCl₃): δ 8.95 (dd, 1H), 8.65 (s, 1H), 8.48 (s, 1H), 8.27 (d, 1H), 8.12(m, 2H), 7.80 (s, 1H), 7.72 (s, 1H), 7.61 (d, 1H), 7.50 (m, 4H), 6.48(d, 1H), 6.20 (br s, NH), 2.86 (m, 1H), 2.70 (s, 3H), 2.03 (s, 6H), 0.82(m, 2H), 0.57 (m, 2H).

EXAMPLE 398-[3-(3—Chloro-pyrazin-2-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

A mixture of Quinoline 4 (1.0 eq.), 2,3-dichloro-pyrazine (3.0 eq.),Pd(IMes)₂ (0.05 eq.) and Na₂CO₃ (2M, 3.5 eq.) in 1,4-dioxane (0.2M) wasstirred at 100° C. for 2 h. The mixture was cooled to rt, poured insaturated aqueous NH₄Cl and extracted with EtOAc (2×). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Flash chromatography (Hex:EtOAc; 7:3) afforded the titlecompound as a white solid. ¹H NMR (500 MHz, acetone-d₆): δ 8.94 (dd,1H), 8.72 (d, 1H), 8.47 (m, 1H), 8.46 (dd, 1H), 8.32 (d, 1H), 8.25 (m,2H), 7.92 (d, 1H), 7.89 (d, 1H), 7.66 (t, 1H), 7.57 (dd, 1H), 2.74 (s,3H), 2.02 (s, 6H).

EXAMPLE 408-(3-Benzo[1,2,5]oxadiazol-5-ylphenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Prepared according to the procedure described in EXAMPLE 3, but using5-Bromo-benzo[1,2,5]oxadiazole (Biorg. Med. Chem. Lett. 2002, 233) asstarting material. The reaction mixture was stirred 12 h at 80° C. Flashchromatography (Hex:EtOAc 5 to 50% in 20 min) and crystallization inHex:EtOAc afforded the title compound as a white solid. ¹H NMR (500 MHz,acetone-d₆): δ 8.98 (dd, 1H), 8.52 (dd, 1H), 8.35 (d, 1H), 8.28 (d, 1H),8;26 (t, 1H), 8.23 (t, 1H), 8.11 (dd, 1H), 8.08 (dd, 1H), 7.93 (dd, 1H),7.89 (dd, 1H), 7.71 (t, 1H), 7.63 (dd, 1H), 2.76 (s, 3H), 2.04 (s, 6H).

EXAMPLE 41N-(5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridin-2-yl)-acetamide

Step 1: N-(5-Bromo-pyridin-2-yl)-acetamide

To a solution of 5-bromo-pyridin-2-ylamine (1.0 eq.), Net₃ (1.2 eq.) inCH₂Cl₂ (0.1M) was added AcCI (1.2 eq.). The mixture was stirred 1 h atrt, poured in saturated aqueous NH₄Cl and extracted with EtOAc (2×). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated. Flash chromatography (CH₂Cl₂:EtOAc; 85:15)afforded the title compound as a white solid.

Step 2: N-(5-Bromo-1-oxy-pyridin-2-yl)-acetamide

Prepared according to the procedure described in EXAMPLE 9, Step 4, butusing N-(5-bromo-pyridin-2-yl)-acetamide from Step 1 as startingmaterial. Flash chromatography (EtOAc) afforded the title compound as awhite solid.

Step 3: EXAMPLE 41

Prepared according to the procedure described in EXAMPLE 6, Step 2, butusing N-(5-bromo-1-oxy-pyridin-2-yl)-acetamide from Step 2 as startingmaterial. The reaction mixture was stirred 1.5 h at 90° C. Flashchromatography (EtOAc:EtOH; 85:15) afforded the title compound as awhite solid. ¹H NMR (500 MHz, acetone-d₆): δ 10.15 (s, NH), 8.94 (dd,1H), 8.60 (d, 1H), 8.49-8.43 (m, 2H), 8.32 (d, 1H), 8.21 (d, 1H), 8.06(s, 1H), 7.80-7.73 (m, 3H), 7.65-7.57 (m, 2H), 2.72 (s, 3H), 2.36 (s,3H), 2.01 (s, 6H).

EXAMPLE 422-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-cyclopropanecarboxylicacid

Step 1: Trans-2-(4-Bromo-phenyl)-cyclopropanecarboxylic acid ethyl ester

To a solution of E-3-(4-bromo-phenyl)-acrylic acid ethyl ester andPd(OAc)₂ (0.05 eq.) in THF (0.2M) was added portionwise CH₂N₂ until thereaction was completed. NMR of aliquots monitored the reaction. Theresulting mixture was concentrated and filtered on celite to afford thetitle compound as an oil.

Step 2:Trans-2-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl)}-cyclopropanecarboxylicacid ethyl ester

Prepared according to the procedure described in EXAMPLE 6, Step 2, butusing 2-(4-bromo-phenyl)-cyclopropanecarboxylic acid ethyl ester fromStep 2 as starting material. The reaction mixture was stirred 2 h at100° C. Flash chromatography (Hex:EtOAc 3:2) afforded the title compoundas a foam.

Step 3: EXAMPLE 42

To a solution of2-{3′[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl4-yl}-cyclopropanecarboxylic acid ethyl ester (1.0 eq.) from Step 1, inTHF:MEOH (2:1; 0.2M) was added aqueous LiOH (2M; 0.2.0 eq.). The mixturewas stirred for 12 h at rt, quenched with HCl 10% and extracted withEtOAc (2×). The combined organic extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated. Crystallization in Hex:EtOAcafforded the title compound as a white solid. ¹H NMR (400 MD,acetone-d₆): δ 8.96 (dd, 1H), 8.50 (dd, 1H), 8.32 (d, 1H), 8.24 (d, 1H),8.03 (t, 1H), 7.73-7.68 (m, 4H), 7.63-7.59 (m, 2H), 7.32 (d, 2H), 2.75(s, 3H), 2.53 (m, 1H), 2.03 (s, 6H), 1.97 (m, 1H), 1.56 (m, 1H), 1.46(m, 1H).

The enantiomers of EXAMPLE 42 were isolated separately by the followingprocedure.

Step 4: E-3-(4-Bromo-phenyl)-1-imidazol-1-yl-propenone

To a solution of E-3-(4-Bromo-phenyl)-acrylic acid (1.0 eq.) in toluene(0.2M) was added CDI (1.5 eq.). The mixture was stirred for 3 h at rt.The resulting precipitate was isolated by filtration to afford the titlecompound as a white solid.

Step 5:E-3-[3-(4-Bromo-phenyl)-acryloyl]-4-methyl-5-phenyl-oxazolidin-2-one

A mixture of 3-(4-Bromo-phenyl)-1-imidazol-1-yl-propenone (1.05 eq.)from Step 4, (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (1.0 eq.) andEt3N (1.2 eq) in CH₃CN (0.2M) was reflux overnight. The resultingmixture was cooled to rt, filtered on a pad of silica gel andconcentrated. Crystallization in Hex:Et₂O afforded the title compound asa white solid.

Step 6:Trans-3-[2-(4-Bromo-phenyl)-cyclopropanecarbonyl]-4-methyl-5-phenyl-oxazolidin-2-one

To a solution ofE-3-[3-(4-Bromo-phenyl)-acryloyl]4-methyl-5-phenyl-oxazolidin-2-one fromStep 5 and Pd(OAc)₂ (0.05 eq.) in THF (0.2M) was added portionwise CH₂N₂until the reaction was completed. NMR of aliquots monitored thereaction. The resulting mixture was concentrated and flashchromatography (Hex:EtOAc; 3:2) to afford the two separatediastereoisomers. Each diastereoisomers were submitted to the proceduresdescribed in Step 2 and Step 3 to afford the (+) and (−) enantiomers ofEXAMPLE 42

EXAMPLE 432-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-biphenyl-4-yl}-2-methyl-propionicacid

Step 1: 2-(4-Bromophenyl)-2-methyl-propionic acid methyl ester

To a solution of (4-Bromo-phenyl)-acetic acid methyl ester (1.0 eq) inDMF (0.2M) was added MeI (20 eq) followed by NaH (2.2 eq.) portion wise.The mixture was stirred for 2 h. An extra amount of NaH (1.1 eq) wasadded. The final mixture was stirred for 12 h, poured in saturatedaqueous NH₄Cl and extracted with Et₂O (2×). The combined organicextracts were washed with water (3×), brine, dried over MgSO₄, filteredand concentrated. Flash chromatography (Hex:EtOAc; 95:5) afforded thetitle compound as a foam.

Step 2:3-{3′-[6-(1-Methanesulfonyl-1-methylethyl)-quinolin-8-yl]-biphenyl-4-yl}-3-methyl-butyricacid methyl ester

Prepared according to the procedure described in EXAMPLE 6, Step 2, butusing 2-(4-bromo-phenyl)-2-methyl-propionic acid methyl ester from Step1 as starting material. The reaction mixture was stirred 2 h at 70° C.Flash chromatography (Hex:EtOAc; 3:2) afforded the title compound as afoam.

Step 3: EXAMPLE 43

To a solution of3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-3-methyl-butyricacid methyl ester (1.0 eq.) from Step 1, in THF:MeOH (2:1; 0.2M) wasadded aqueous LiOH (2M; 5.0 eq.). The mixture was stirred for 4 h at 60°C., quenched with AcOH (20 eq.), poured in brine and extracted withEtOAc (2×). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated. Crystallization in Hex:Et₂O:EtOAc affordedthe title compound as a white solid. ¹H NMR (500 MHz, acetone-d₆): δ8.93 (dd, 1H), 8.46 (dd, 1H), 8.29 (d, 1H), 8.21 (d, 1H), 8.02 (t, 1H),7.72-7.68 (m, 4H), 7.59-7.51 (m, 4H), 2.72 (s, 3H), 2.00 (s, 6H), 1.59(s, 6H).

EXAMPLE 441-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-cyclopropanecarboxylicacid

Step 1:1-(4-Bromo-phenyl)-cyclopropanecarbonitrile (See Org Prep. andProc., 1995, 27, 355.)

A mixture of (4-bromo-phenyl)-acetonitrile (1.0 eq.),1-bromo-2-chloro-ethane (1.6 eq.), triethylbenzyl ammonium chloride(0.03 eq.) and aqueous NaOH 50% (6 eq.) was stirred for 12 h at 60° C.The resulting mixture was poured in water and extracted with Et₂O (2×).The combined organic extracts were washed with HCl 5%, brine, dried overMgSO₄, filtered and concentrated. Flash chromatography (Hex:EtOAc; 95:5)afforded the title compound as a foam.

Step 2: 1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid methyl ester

To a solution of -(4-bromo-phenyl)-cyclopropanecarbonitrile from Step 1in EtOH (0.2M) was added NaOH 25% (10 eq.). The mixture was stirred for6 h at 100° C., quenched with AcOH (20 eq.), poured in brine, extractedwith EtOAc (2×). The combined organic extracts were dried over MgSO₄,filtered and concentrated. The residue was dissolved in CH₂Cl₂ anddiazomethane was added portionwise until the esterification wascompleted by TLC. Flash chromatography (Hex:EtOAc; 9:1) afforded thetitle compound as a colorless oil.

Step 3:1{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-cyclopropanecarboxylicacid methyl ester

Prepared according to the procedure described in EXAMPLE 6, Step 2, but1-(4-bromo-phenyl)-cyclopropanecarboxylic acid methyl ester from Step 2as starting material. The reaction mixture was stirred 2 h at 70° C.Flash chromatography (Hex:EtOAc; 2:1) afforded the title compound as afoam.

Step 4: EXAMPLE 44

Prepared according to the procedure described in EXAMPLE 43, Step 3, butusing1-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-cyclopropanecarboxylicacid methyl ester from Step 3 as starting material. Crystallization inHex:Et₂O afforded the title compound as a white solid. ¹H NMR (500 MHz,acetone-d₆): δ 8.96 (dd, 1H), 8.50 (dd, 1H), 8.32 (d, 1H), 8.24 (d, 1H),8.04 (t, 1H), 7.75-7.72 (m, 2H), 7.69 (d, 2H), 7.62-7.58 (m, 2H), 7.51(d, 2H), 2.75 (s, 3H), 2.03 (s, 6H), 1.59 (dd, 2H), 1.26 (dd, 2H).

EXAMPLE 453-13′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4yl)-2,2-dimethyl-propionicacid

Step 1: 3-(4-Bromo-phenyl)-propionic acid tert-butyl ester

To a solution of cyclohexyl-isopropyl-amine (1.0 eq.) in THF (2.0M) at−78° C. was added dropwise n-BuLi (0.95eq.). The mixture was stirred at−78° C. for 20 min then a solution of acetic acid tert-butyl ester (1.0eq.) in THF (5.0M) was added dropwise. The resulting mixture was stirredat −78° C. for 1 h. A solution of 4-bromobenzyl bromide (0.9eq.) in THF(5.0M) was then added dropwise and the final mixture was warm slowly tort and stirred for 12 h. The reaction was quenched with cold aqueous HCl(1M), diluted water and extracted with Et₂O (2×). The combined organicextracts were washed with HCl (1M), brine, dried over Na₂SO₄, filteredand concentrated. The residue was distilled under vacuum (95° C., 0.4mmHg) to afford the title compound as a colorless oil.

Step 2: 3-(4-Bromo-phenyl)-2,2-dimethyl-propionic acid tert-butyl ester

To a solution of cyclohexyl-isopropyl-amine (1.2eq.) in THF (1.0M) at−78° C. was added dropwise n-BuLi (1.2eq.). The mixture was stirred at−78° C. for 20 min then a solution of 3-(4-bromo-phenyl)-propionic acidtert-butyl ester from Step 1 (1.0 eq.) in THF (5.0M) was added dropwise.The resulting mixture was stirred at −78° C. for 30 min then MeI (5.0eq.) was added. The final mixture was warm slowly to rt and stirred for1 h. The reaction was poured in cold aqueous HCl (0.5M) and extractedwith Et₂O (2×). The combined organic extracts were washed with brine,dried over MgSO₄, filtered and concentrated. The residue was resubmittedthrice to the above procedure until no mono-methyl compound was observedby NMR. Flash chromatography (Hex:EtOAc; 95:5) afforded the titlecompound as a colorless oil.

Step 3:3-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-2,2-dimethyl-propionicacid tert-butyl ester

Prepared according to the procedure described in EXAMPLE 6, step 2, but3-(4-Bromo-phenyl)-2,2-dimethyl-propionic acid tert-butyl ester fromStep 2 as starting material. The reaction mixture was stirred 2 h at 70°C. Flash chromatography (Hex:EtOAc 30 to 90% in 20 min) afforded thetitle compound as a foam.

Step 4: EXAMPLE 45

A solution of3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4yl}-2,2-dimethyl-propionicacid tert-butyl ester from Step 3 in CH₂Cl₂:TFA (2:1) was stirred at rtfor 12 h. The resulting mixture was concentrated and diluted with water.The pH was adjusted to 5 using first NaOH (1M) then excess AcOH. Theaqueous phase was extracted with EtOAc (2×). The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Crystallization in Hex:CH₂Cl₂ afforded the title compoundas a white solid. ¹H NMR (500 MHz, acetone-d₆): δ 8.93 (dd, 1H), 8.46(dd, 1H), 8.29 (d, 1H), 8.21 (d, 1H), 8.00 (t, 1H), 7.71-7.68 (m, 2H),7.63 (d, 2H), 7.59-7.54 (m, 2H), 7.32 (d, 2H), 2.93 (s, 2H), 2.72 (s,3), 2.00 (s, 6H), 1.19 (s, 6H).

EXAMPLE 462-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-cyclopropanecarboxylicacid

Step 1: Z-3-(4-Bromo-phenyl)-acrylic acid methyl ester (Tett Lett. 1983,4405)

To a solution of [Bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acidmethyl ester (1.0 eq.) and 18—C-6 (5.0 eq.) in THF (0.05M) at −78° C.was added dropwise KN(TMS)₂ (1.0 eq.). The mixture was stirred at −78°C. for 15 min then 4-bromobenzaldehyde (1.0 eq.) was added. The finalmixture stirred for 1 h at −78° C., poured in saturated aqueous NH₄Cland extracted with Et₂O (3×). The combined organic extracts were washedwith, brine, dried over Na₂SO₄, filtered and concentrated. Flashchromatography (Hex:EtOAc 10 to 25%) afforded a mixture of desiredmaterial and the starting aldehyde. Upon treatment in CH₂Cl₂ of themixture with Amino-Merrifield resin for 10 min, the aldehyde wasremoved. Filtration and concentration afforded the title compound as anoil.

Step 2: Cis-2-(4-Bromo-phenyl)-cyclopropanecarboxylic acid ethyl ester

Prepared according to the procedure described in Example 42, Step 1, butusing Z-3-(4-Bromo-phenyl)-acrylic acid methyl ester from Step 1 asstarting material Flash chromatography (Hex:EtOAc 85:15) afforded thetitle compound as a oil.

Step 3: C is2-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-cyclopropanecarboxylicacid methyl ester

Prepared according to the procedure described in EXAMPLE 6, Step 2, butusing 2-(4-bromo-phenyl)-cyclopropanecarboxylic acid ethyl ester fromStep 2 and PdCl₂(dppf)₂ as starting materials. The reaction mixture wasstirred 2 h at 60° C. Flash chromatography (Hex:EtOAc 35 to 50%)afforded the title compound as a foam.

Step 4: EXAMPLE 46

Prepared according to the procedure described in EXAMPLE 42, Step 3, butusing C is2-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-cyclopropanecarboxylicacid methyl ester from Step 3 as starting materials. Crystallization inEt₂O afforded the title compound as a white solid. ¹H NMR (500 MHz,acetone-d₆): δ 8.95 (dd, 1H), 8.49 (dd, 1H), 8.32 (d, 1H), 8.23 (d, 1H),8.02 (t, 1H), 7.73-7.69 (m, 2H), 7.64-7.57 (m, 4H), 7.41 (d, 2H), 2.75(s, 3H), 2.71-2.67 (m, 1H), 2.20-2.11 (m, 1H), 2.03 (s, 6H), 1.69-1.65(m, 1H), 1.43-1.39 (m, 1H).

EXAMPLE 473-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-3-methyl-butyricacid

Step 1: 3-(4-Iodo-phenyl)-3-methyl-butyric acid methyl ester

The corresponding acid was prepared according to the procedure J. Am.Chem. Soc. 1948, 70, 370 and was converted to the title singdiazomethane in CH₂Cl₂.

Step2:3-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-3-methyl-butyricacid methyl ester

Prepared according to the procedure described in EXAMPLE 6, Step 2, butusing 3-(4-Iodo-phenyl)-3-methyl-butyric acid methyl ester from Step 1as starting material. The reaction mixture was stirred 2.5 h at 70° C.Flash chromatography (Hex:EtOAc 1:1) afforded the title compound as afoam.

Step 3: EXAMPLE 47

Prepared according to the procedure described in EXAMPLE 43, Step 3, butusing3-{3′[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-3-methyl-butyricacid methyl ester from Step 2 as starting material. Crystallization inHex:EtOAc afforded the title compound as a white solid. ¹H NMR (500 MHz,acetone-d₆): δ 8.93 (dd, 1H), 8.46 (dd, 1H), 8.29 (d, 1H), 8.22 (d, 1H),802 (t, 1H), 7.74-7.65 (m, 4H), 7.61-7.53 (m, 4H), 2.73 (s, 3H), 2.70(s, 2H), 2.01 (s, 6H), 1.49 (s, 6H).

The following compounds were prepared according to the proceduredescribed previously. Indicated is their respective (M+1)⁺ valueobtained from a low resolution mass spectrometer under electron-sprayionization conditions. ESI- LRMS (M + EX. Chemical name 1)⁺ 486-Isopropyl-8-(4′-methanesulfonyl-biphenyl-3-yl)- 402.4 quinoline 491-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 444.3quinolin-8-yl]-biphenyl-3-yl}-ethanone 501-{3-Hydroxy-3′-[6-(1-methanesulfonyl-1-methyl- 460.3ethyl)-quinolin-8-yl]-biphenyl-4-yl}-ethanone 511-{4-Hydroxy-3′-[6-(1-methanesulfonyl-1-methyl- 460.3ethyl)-quinolin-8-yl]-biphenyl-3-yl}-ethanone 528-(3′-Methanesulfonyl-biphenyl-3-yl)-6-(1- 480.2methanesulfonyl-1-methyl-ethyl)-quinoline 538-(4′-Methanesulfonyl-biphenyl-3-yl)-6-(1- 480.2methanesulfonyl-1-methyl-ethyl)-quinoline 546-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(5- 471.3trifluoromethyl-pyridin-2-yl)-phenyl]-quinoline 556-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(3-methyl- 417.3pyridin-2-yl)-phenyl]-quinoline 566-(1-Methanesulfonyl-1-methyl-ethyl)-8-(3-thiophen- 408.32-yl-phenyl)-quinoline 57 1-(5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-450.4 quinolin-8-yl]-phenyl}-thiophen-2-yl)-ethanone 586-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(3-methyl- 422.3thiophen-2-yl)-phenyl]-quinoline 595-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 487.38-yl]-phenyl}-thiophene-2-sulfonic acid amide 603′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8- 427.3yl]-biphenyl-4-carbonitrile 616-(1-Methanesulfonyl-1-methyl-ethyl)-8-(3-quinolin- 453.33-yl-phenyl)-quinoline 626-(1-Methanesulfonyl-1-methyl-ethyl)-8-(3-pyridin-3- 403.3yl-phenyl)-quinoline 636-(1-Methanesulfonyl-1-methyl-ethyl)-8-(3-pyridin-4- 403.3yl-phenyl)-quinoline 646-(1-Methanesulfonyl-1-methyl-ethyl)-8-(3′-nitro- 447.2biphenyl-3-yl)-quinoline 65 8-(3-Benzo[1,3]dioxol-5-yl-phenyl)-6-(1-446.3 methanesulfonyl-1-methyl-ethyl)-quinoline 66{4-Chloro-3′-[6-(1-methanesulfonyl-1-methyl-ethyl)- 466.4quinolin-8-yl]-biphenyl-3-yl}-methanol 676-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(5- 481.3methanesulfonyl-pyridin-3-yl)-phenyl]-quinoline 686-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(6- 449.3methylsulfanyl-pyridin-2-yl)-phenyl]-quinoline 696-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(6- 449.3methylsulfanyl-pyridin-3-yl)-phenyl]-quinoline 703-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 486.3quinolin-8-yl]-biphenyl-3-yl}-acrylic acid methyl ester 713′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8- —yl]-biphenyl-3-carbaldehyde 722,2,2-Trifluoro-1-{3′-[6-(1-methanesulfonyl-1-methyl- 500.3ethyl)-quinolin-8-yl]-biphenyl-3-yl}-ethanol 73{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 432.28-yl]-biphenyl-2-yl}-methanol 743-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 486.4quinolin-8-yl]-biphenyl-2-yl}-acrylic acid methyl ester 758-(2′-Methanesulfonylmethyl-biphenyl-3-yl)-6-(1- 494.3methanesulfonyl-1-methyl-ethyl)-quinoline 766-(1-Methanesulfonyl-1-methyl-ethyl)-8-[2′- 532.3([1,3,4]thiadiazol-2-ylsulfanylmethyl)-biphenyl-3-yl]- quinoline 77{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 432.28-yl]-biphenyl-4-yl}-methanol 783-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- —quinolin-8-yl]-biphenyl-4-yl}-acrylic acid methyl ester 796-(1-Methanesulfonyl-1-methyl-ethyl)-8-[2′-(1- 528.3methyl-1H-imidazol-2-ylsulfanylmethyl)-biphenyl-3- yl]-quinoline 803-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 488.4quinolin-8-yl]-biphenyl-2-yl}-propionic acid methyl ester 813-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 458.4quinolin-8-yl]-biphenyl-2-yl}-prop-2-en-1-ol 823-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 460.3quinolin-8-yl]-biphenyl-2-yl}-propan-1-ol 83{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 432.28-yl]-biphenyl-3-yl}-methanol 842-(6-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 461.5quinolin-8-yl]-phenyl}-pyridin-3-yl)-propan-2-ol 853-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 474.4quinolin-8-yl]-biphenyl-2-yl}-propionic acid 866-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methyl- 337.1pyridin-3-yl)-phenyl]-quinoline 873-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 472.4quinolin-8-yl]-biphenyl-3-yl}-acrylic acid 885-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 475.38-yl]-phenyl}-nicotinic acid ethyl ester 896-(1-Methanesulfonyl-1-methyl-ethyl)-8-{3-[6- 509.4(propane-2-sulfonyl)-pyridin-3-yl]-phenyl}-quinoline 908-[3-(6-Benzyloxy-pyridin-3-yl)-phenyl]-6-(1- 509.3methanesulfonyl-1-methyl-ethyl)-quinoline 912-(5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 461.3quinolin-8-yl]-phenyl}-pyridin-3-yl)-propan-2-ol 923-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 474.4quinolin-8-yl]-biphenyl-3-yl}-propionic acid 936-(1-Methanesulfonyl-1-methyl-ethyl)-8-{3-[5-(2- 535.4trimethylsilanyl-ethylsulfanyl)-pyridin-3-yl]-phenyl}- quinoline 948-{3-[5-(4-Fluoro-benzylsulfanyl)-pyridin-3-yl]- 543.2phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)- quinoline 953-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 472.4quinolin-8-yl]-biphenyl-4-yl}-acrylic acid 96N-Cyclopropyl-5-{3-[6-(1-methanesulfonyl-1-methyl- 486.2ethyl)-quinolin-8-yl]-phenyl}-nicotinamide 973-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 486.38-yl]-phenyl}-5-trifluoromethyl-pyridin-2-ylamine 98Dicyclopropyl-(5-{3-[6-(1-methanesulfonyl-1-methyl- 529.5ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridin-2-yl)- methanol 998-[3-(6-Ethanesulfonyl-pyridin-3-yl)-phenyl]-6-(1- 495.3methanesulfonyl-1-methyl-ethyl)-quinoline 1002-(5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 461.5quinolin-8-yl]-phenyl}-pyridin-2-yl)-propan-2-ol 1016-(1-Methanesulfonyl-1-methyl-ethyl)-8-{3-[1-oxy-5- 583.4(2-trimethylsilanyl-ethanesulfonyl)-pyridin-3-yl]- phenyl}-quinoline 1028-(3-{5-[1,2-Bis-(4-fluoro-phenyl)-ethanesulfonyl]-1- 699.3oxy-pyridin-3-yl}-phenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline 1038-[3-(5-Ethanesulfinyl-1-oxy-pyridin-3-yl)-phenyl]-6- 495.1(1-methanesulfonyl-1-methyl-ethyl)-quinoline 1046-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(1-oxy-5- 487.3trifluoromethyl-pyridin-3-yl)-phenyl]-quinoline 1056-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(6- 495.9methanesulfonyl-5-methyl-pyridin-3-yl)-phenyl]- quinoline 1063-(5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 506.5quinolin-8-yl]-phenyl}-1-oxy-pyridin-2-yl)-pentan-3- ol 107(5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 449.3quinolin-8-yl]-phenyl}-1-oxy-pyridin-3-yl)-methanol 108Difluoro-(5-{3-[6-(1-methanesulfonyl-1-methyl- 557.2ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-ylsulfanyl)- acetic acid ethylester 109 Difluoro-(5-{3-[6-(1-methanesulfonyl-1-methyl- 529.4ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-ylsulfanyl)- acetic acid 110(5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 449.3quinolin-8-yl]-phenyl}-1-oxy-pyridin-2-yl)-methanol 1116-(1-Methanesulfonyl-1-methyl-ethyl)-8-(5-phenyl- 404.3pyridin-3-yl)-quinoline 1126-(1-Methanesulfonyl-1-methyl-ethyl)-8-(1-oxy-5- 420.0phenyl-pyridin-3-yl)-quinoline 1131-Isopropyl-3-(5-{3-[6-(1-methanesulfonyl-1-methyl- 502.6ethyl)-quinolin-8-yl]-phenyl}-pyridin-2-yl)-urea 1146-(1-Methanesulfonyl-1-methyl-ethyl)-8-{3-[5-(2- 567.4trimethylsilanyl-ethanesulfonyl)-pyridin-3-yl]- phenyl}-quinoline 1158-[3-(4-Chloro-pyridin-3-yl)-phenyl]-6-(1- 437.3methanesulfonyl-1-methyl-ethyl)-quinoline 116(5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 553.5quinolin-8-yl]-phenyl}-pyridin-2-yl)-(4-methylsulfanyl-phenyl)-methanone 1175-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 504.48-yl]-phenyl}-1-oxy-pyridine-2-carboxylic acid isopropylamide 1183′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8- 427.3yl]-biphenyl-2-carbonitrile 1196-(1-Methanesulfonyl-1-methyl-ethyl)-8-(2′- 448.2methylsulfanyl-biphenyl-3-yl)-quinoline 1208-(2′-Methanesulfonyl-biphenyl-3-yl)-6-(1- 480.2methanesulfonyl-1-methyl-ethyl)-quinoline 1211,1,1,3,3,3-Hexafluoro-2-(5-{3-[6-(1- 569.7methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-yl)-propan-2-ol 1226-(1-Methanesulfonyl-1-methyl-ethyl)-8-{3-[6-(4- 539.4methoxy-benzyloxy)-pyridin-2-yl]-phenyl}-quinoline 1236-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 419.38-yl]-phenyl}-1H-pyridin-2-one 124 1,1,1,3,3,3-Hexafluoro-2-(5-{3-[6-(1-585.5 methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridin-3-yl)-propan-2-ol 1255-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 447.28-yl]-phenyl}-nicotinic acid 126 1,1,1,3,3,3-Hexafluoro-2-(5-{3-[6-(1-585.5 methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridin-2-yl)-propan-2-ol 1275-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 477.28-yl]-phenyl}-1-oxy-pyridine-2-carboxylic acid methyl ester 1285-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 463.28-yl]-phenyl}-1-oxy-pyridine-2-carboxylic acid 129{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 460.38-yl]-biphenyl-3-yl}-acetic acid 1303′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8- 446.3yl]-biphenyl-3-carboxylic acid 1315-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 463.28-yl]-phenyl}-1-oxy-nicotinic acid 1323-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 488.4quinolin-8-yl]-biphenyl-4-yl}-propionic acid methyl ester 1333-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 474.4quinolin-8-yl]-biphenyl-4-yl}-propionic acid 1342-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 514.4quinolin-8-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl ester135 5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 444.38-yl]-phenyl}-1-oxy-nicotinonitrile 1363′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8- 445.2yl]-biphenyl-3-carboxylic acid amide 1372-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 486.4quinolin-8-yl]-biphenyl-3-yl}-cyclopropanecarboxylic acid 1385-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 577.48-yl]-phenyl}-1-oxy-nicotinic acid 2,2-dimethyl- propionyloxymethylester 139 3-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 544.4quinolin-8-yl]-biphenyl-4-yl}-2-methyl-propionic acid tert-butyl ester140 3-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 488.4quinolin-8-yl]-biphenyl-4-yl}-2-methyl-propionic acid 1412-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 502.2quinolin-8-yl]-biphenyl-4-yl}-2-methyl-propionic acid methyl ester 142{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin- 460.38-yl]-biphenyl-4-yl}-acetic acid 1431-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 485.3quinolin-8-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid amide 1442-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 488.4quinolin-8-yl]-biphenyl-3-yl}-2-methyl-propionic acid 1458-[3-(5-Chloro-1-oxy-pyridin-3-yl)-phenyl]-6-(1- 453.3methanesulfonyl-1-methyl-ethyl)-quinoline 146(1-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 560.3quinolin-8-yl]-biphenyl-4-ylmethylsulfanylmethyl}- cyclopropyl)-aceticacid 147 (1-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 592.3quinolin-8-yl]-biphenyl-4-ylmethanesulfonyl-methyl}- cyclopropyl)-aceticacid 148 3-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 486.4quinolin-8-yl]-biphenyl-4-yl}-acrylic acid methyl ester 1491-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 514.4quinolin-8-yl]-biphenyl-4-ylmethyl}- cyclobutanecarboxylic acid 150[1-(5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 547.4quinolin-8-yl]-phenyl}-pyridin-2-ylsulfanylmethyl)- cyclopropyl]-aceticacid 151 [1-(5-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 579.4quinolin-8-yl]-phenyl}-pyridine-2-sulfonylmethyl)- cyclopropyl]-aceticacid 152 6-(1-Methanesulfonyl-1-methyl-ethyl)-8-{4′-[2-(1H- 510.3tetrazol-5-yl)-cyclopropyl]-biphenyl-3-yl}-quinoline 153(1-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 546.2quinolin-8-yl]-biphenyl-4-ylsulfanylmethyl}- cyclopropyl)-acetic acid154 (1-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 578.4quinolin-8-yl]-biphenyl-4-sulfonylmethyl}- cyclopropyl)-acetic acid 1553-{3′-[6-(1-Methanesulfonyl-1-methyl-ethyl)- 472.4quinolin-8-yl]-biphenyl-4-yl}-acrylic acid

Other variations or modifications, which will be obvious to those theart, are within the scope and teachings of this invention. Thisinvention e limited except as set forth in the following claims.

1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein A is C or N; X isphenyl, pyridyl, pyrazinyl, thiaphenyl, quinolinyl, benzofuranyl,oxadiazolyl, diazolylpyridinyl, imidazolylpyridinyl, oxadiazolylphenyl,or benzodioxolyl; R₁ is hydrogen, halogen; or —C₁₋₆alkyl,-cycloC₃₋₆alkyl, or —C₁₋₆alkenyl group, wherein any of the groups isoptionally substituted with 1-6 substituents; wherein each substituentis independently halogen, —OH, —CN, or —SO₂—C₁₋₆alkyl; R₂, and R₃ areeach independently hydrogen, halogen, hydroxyl, —CN, —NO₂; or—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl(C₂₋₆alkenyl)₂,—C₀₋₄alkyl(C₃₋₆cycloalkyl)₂, —C₀₋₆alkyl-N(C₀₋₆alkyl)₂,—C₀₋₄alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-phenyl, —C₀₋₆alkyl-SO₂—C₁₋₆alkyl,—C₀₋₆alkyl-C(O)—C₀₋₄alkyl, —C₀₋₆alkyl(O)—C₀₋₆alkyl-phenyl,—C₀₋₆alkyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,—C₀₋₆alkyl-C(O)C₀₋₆alkyl-O—C₀₋₆alkyl-O—C₀₋₆alkyl-C(O)C₀₋₆alkyl,—C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-O—C₀₋₆alkyl, C₀₋₄alkyl,C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)—C₀₋₆alkyl,—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₆alkyl-N(C₀₋₆alkyl)₂,—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₆alkyl-C(O)C₀₋₄alkyl-O—C₀₋₆alkyl,—C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₆alkyl)pyridyl,—C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)₂,—C₀₋₆alkyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl—C₂₋₆alkenyl-C(O)—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₃₋₆cycloalkyl,—SO₂—C₀₋₆alkyl-phenyl,—SO₂—C₀₋₆alkyl-C₀₋₆alkyl-phenyl)(C₀₋₆alkyl-phenyl),—C₀₋₄alkyl-SO₂—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl,—S(O)—C₀₋₆alkyl, —P(O)(O)—C₀₋₄alkyl)(O)—C₀₋₄alkyl),—C₂₋₆alkenyl-C(O)C₀₋₄alkyl-N(C₀₋₄alkyl)pyridyl, —S—C₁₋₆alkyl,—C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)—C₀₋₆alkyl,—C₀₋₆alkyl-N(C₀₋₆alkyl)—C(O)N(C₀₋₆alkyl)₂,—C₀₋₄alkyl-S—C₁₋₄alkyl-oxadiazolyl(C₀₋₄alkyl),—C₀₋₄alkyl(O)—C₀₋₄alkyl-phenyl, —C₀₋₄alkyl-O—C₀₋₄alkyl-phenyl,—C₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-tetrazolyl, —SO₂—N(C₀₋₄alkyl)₂,—C₀₋₄alkyl-S—C₀₋₄alkyl-thiadiazolyl(C₀₋₄alkyl),—C₀₋₄alkyl-S—C₀₋₄alkyl-diazolyl(C₀₋₄alkyl),—C₀₋₄alkyl-S—C₁₋₄alkyl-Si(C₀₋₄alkyl)₃,—C₀₋₄alkyl-S—C₀₋₄alkyl-phenyl(C₀₋₄alkyl),—C₀₋₄alkyl-S—C₀₋₄alkyl-C(O)—C₀₋₄alkyl-O—C₀₋₄alkyl, or—C₀₋₄alkyl-S—₀₋₄alkyl-C₃₋₆cycloalkyl-C₀₋₄alkyl-C(O)C₀₋₄alkyl-O—C₀₋₄alkyl,wherein any alkyl, cycloalkyl, alkenyl, phenyl, or pyridyl are eachoptionally substituted with 1-9 independently halogen, hydroxyl,—C₀₋₄alkyl-O—C ₁₋₆alkyl, or —C₀₋₄alkyl-S—C₁₋₆alkyl; optionally, R₂ forms═O with an adjoining bond; R₄ is hydrogen, or halogen; and any ringnitrogen optionally forms N-oxide or N-chloride.
 2. The compoundaccording to claim 1, wherein A is C.
 3. The compound according to claim2, wherein X is phenyl.
 4. The compound according to claim 2, wherein Xis thiaphenyl.
 5. The compound according to claim 2, wherein X isbenzofuranyl.
 6. The compound according to claim 2, wherein X ispyridyl.
 7. The compound according to claim 2, wherein X is pyridyl and8. The compound according to claim 2, wherein X is quinolinyl.
 9. Thecompound according to claim 2, wherein X is oxadiazolyl.
 10. Thecompound according to claim 2, wherein X is diazolylpyridinyl orimidazolylpyridinyl.
 11. The compound according to claim 2, wherein X ispyrazinyl.
 12. The compound according to claim 2, wherein X isoxadiazolylphenyl.
 13. The compound according to claim 2, wherein X isbenzodioxolyl.
 14. The compound according to claim 1, wherein A is N.15. The compound according to claim 14, wherein X is phenyl.
 16. Thecompound according to claim 1, represented by

or a pharmaceutically acceptable salt thereof.
 17. The compoundaccording to claim 1, represented by

or a pharmaceutically acceptable salt thereof.
 18. The compoundaccording to claim 1, represented by

or a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to claim 1, consisting of6-isopropyl-8-(4′-methanesulfonyl-biphenyl-3-yl)-quinoline;1-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-ethanone;1-{3-hydroxy-3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-ethanone;1-{4-hydroxy-3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-ethanone;8-(3′-methanesulfonyl-biphenyl-3-yl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline;8-(4′-methanesulfonyl-biphenyl-3-yl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline;3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-carbonitrile;6-(1-methanesulfonyl-1-methyl-ethyl)-8-(3′-nitro-biphenyl-3-yl)-quinoline;{4-chloro-3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-methanol;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-acrylicacid methyl ester;3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-carbaldehyde;2,2,2-trifluoro-1-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-ethanol;{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-2-yl}-methanol;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-2-yl}-acrylicacid methyl ester;8-(2′-methanesulfonylmethyl-biphenyl-3-yl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline;6-(1-methanesulfonyl-1-methyl-ethyl)-8-[2′-([1,3,4]thiadiazol-2-ylsulfanylmethyl)-biphenyl-3-yl]-quinoline;{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-methanol;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-acrylicacid methyl ester;6-(1-methanesulfonyl-1-methyl-ethyl)-8-[2′-(1-methyl-1H-imidazol-2-ylsulfanylmethyl)-biphenyl-3-yl]-quinoline;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-2-yl}-propionicacid methyl;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-2-yl}-prop-2-en-1-ol;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-2-yl}-propan-1-ol;{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-methanol;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-2-yl}-propionicacid;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-acrylicacid;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-propionicacid;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-acrylicacid;3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-2-carbonitrile;6-(1-methanesulfonyl-1-methyl-ethyl)-8-(2′-methylsulfanyl-biphenyl-3-yl)-quinoline;8-(2′-methanesulfonyl-biphenyl-3-yl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline;{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-aceticacid;3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-carboxylicacid;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-propionicacid methyl ester;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-propionicacid;2-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-cyclopropanecarboxylicacid methyl ester;3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-carboxylicacid amide;2-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-cyclopropanecarboxylicacid;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-2-methyl-propionicacid tert-butyl ester;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-2-methyl-propionicacid;2-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-2-methyl-propionicacid methyl ester;{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-aceticacid;1-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-cyclopropanecarboxylicacid amide;2-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-2-methyl-propionicacid;(1-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-ylmethylsulfanylmethyl}-cyclopropyl)-aceticacid;(1-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-ylmethanesulfonyl-methyl}-cyclopropyl)-aceticacid;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-acrylicacid methyl ester;1-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-ylmethyl}-cyclobutanecarboxylicacid;6-(1-methanesulfonyl-1-methyl-ethyl)-8-{4′-[2-(1H-tetrazol-5-yl)-cyclopropyl]-biphenyl-3-yl}-quinoline;(1-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-ylsulfanylmethyl}-cyclopropyl)-aceticacid;(1-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-sulfonylmethyl}-cyclopropyl)-aceticacid;3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-acrylicacid; or a pharmaceutically acceptable salt thereof.
 20. The compoundaccording to claim 1, consisting of6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-quinoline;6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(3-methyl-pyridin-2-yl)-phenyl]-quinoline;6-(1-methanesulfonyl-1-methyl-ethyl)-8-(3-pyridin-3-yl-phenyl)-quinoline;6-(1-methanesulfonyl-1-methyl-ethyl)-8-(3-pyridin-4-yl-phenyl)-quinoline;6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(5-methanesulfonyl-pyridin-3-yl)-phenyl]-quinoline;6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methylsulfanyl-pyridin-2-yl)-phenyl]-quinoline;6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methylsulfanyl-pyridin-3-yl)-phenyl]-quinoline;2-(6-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-yl)-propan-2-ol;6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methyl-pyridin-3-yl)-phenyl]-quinoline;5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-nicotinicacid ethyl ester;6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[6-(propane-2-sulfonyl)-pyridin-3-yl]-phenyl}-quinoline;8-[3-(6-benzyloxy-pyridin-3-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline;2-(5-{3-[6-(1-methanesulfonyl--methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-yl)-propan-2-ol;6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[5-(2-trimethylsilanyl-ethylsulfanyl)-pyridin-3-yl]-phenyl}-quinoline;8-{3-[5-(4-fluoro-benzylsulfanyl)-pyridin-3-yl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline;N-cyclopropyl-5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-nicotinamide;3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-5-trifluoromethyl-pyridin-2-ylamine;dicyclopropyl-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridin-2-yl)-methanol;8-[3-(6-ethanesulfonyl-pyridin-3-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline;2-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-2-yl)-propan-2-ol;6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[1-oxy-5-(2-trimethylsilanyl-ethanesulfonyl)-pyridin-3-yl]-phenyl}-quinoline;8-(3-{5-[1,2-bis-(4-fluoro-phenyl)-ethanesulfonyl]-1-oxy-pyridin-3-yl}-phenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline;8-[3-(5-ethanesulfinyl-1-oxy-pyridin-3-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline;6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(1-oxy-5-trifluoromethyl-pyridin-3-yl)-phenyl]-quinoline;6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(6-methanesulfonyl-5-methyl-pyridin-3-yl)-phenyl]-quinoline;3-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridin-2-yl)-pentan-3-ol;(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridin-3-yl)-methanol;difluoro-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-ylsulfanyl)-aceticacid ethyl ester;difluoro-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-ylsulfanyl)-aceticacid;(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridin-2-yl)-methanol;1-isopropyl-3-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-2-yl)-urea;6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[5-(2-trimethylsilanyl-ethanesulfonyl)-pyridin-3-yl]-phenyl}-quinoline;8-[3-(4-chloro-pyridin-3-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline;(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-2-yl)-(4-methylsulfanyl-phenyl)-methanone;5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridine-2-carboxylicacid isopropylamide;1,1,1,3,3,3-hexafluoro-2-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-yl)-propan-2-ol;6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[6-(4-methoxy-benzyloxy)-pyridin-2-yl]-phenyl}-quinoline;1,1,1,3,3,3-hexafluoro-2-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridin-3-yl)-propan-2-ol;5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-nicotinicacid;1,1,1,3,3,3-hexafluoro-2-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridin-2-yl)-propan-2-ol;5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridine-2-carboxylicacid methyl ester;5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-pyridine-2-carboxylicacid;5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-nicotinicacid;5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-nicotinonitrile;5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-oxy-nicotinicacid 2,2-dimethyl-propionyloxymethyl ester;8-[3-(5-chloro-1-oxy-pyridin-3-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline;[1-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-2-ylsulfanylmethyl)-cyclopropyl]-aceticacid;[1-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridine-2-sulfonylmethyl)-cyclopropyl]-aceticacid;6-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1H-pyridin-2-oneor a pharmaceutically acceptable salt thereof.
 21. The compoundaccording to claim 1, consisting of6-(1-methanesulfonyl-1-methyl-ethyl)-8-(3-thiophen-2-yl-phenyl)-quinoline;1-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-thiophen-2-yl)-ethanone;6-(1-methanesulfonyl-1-methyl-ethyl)-8-[3-(3-methyl-thiophen-2-yl)-phenyl]-quinoline;5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-thiophene-2-sulfonicacid amide;6-(1-methanesulfonyl-1-methyl-ethyl)-8-(3-quinolin-3-yl-phenyl)-quinoline;8-(3-benzo[1,3]dioxol-5-yl-phenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline;or a pharmaceutically acceptable salt thereof.
 22. The compoundaccording to claim 1, consisting of6-(1-methanesulfonyl-1-methyl-ethyl)-8-(5-phenyl-pyridin-3-yl)-quinoline;6-(1-methanesulfonyl-1-methyl-ethyl)-8-(1-oxy-5-phenyl-pyridin-3-yl)-quinoline;or a pharmaceutically acceptable salt thereof.
 23. A pharmaceuticalcomposition comprising: a therapeutically effective amount of thecompound according to claim 1 or a pharmaceutically acceptable saltthereof; and a pharmaceutically acceptable carrier.
 24. Thepharmaceutical composition according to claim 23, further comprising aLeukotriene receptor antagonist, a Leukotriene biosynthesis inhibitor,or an M2/M3 antagonist.
 25. A method of treatment or prevention ofasthma; chronic bronchitis; chronic obstructive pulmonary disease; adultrespiratory distress syndrome; infant respiratory distress syndrome;cough; chronic obstructive pulmonary disease in animals; adultrespiratory distress syndrome; ulcerative colitis; Crohn's disease;hypersecretion of gastric acid; bacterial, fungal or viral inducedsepsis or septic shock; endotoxic shock; laminitis or colic in horses;spinal cord trauma; head injury; neurogenic inflammation; pain;reperfusion injury of the brain; psoriatic arthritis; rheumatoidarthritis; ankylosing spondylitis; osteoarthritis; inflammation; orcytokine-mediated chronic tissue degeneration comprising the step ofadministering a therapeutically effective amount, or a prophylacticallyeffective amount, of the compound according to claim 1 or apharmaceutically acceptable salt thereof.
 26. A method of treatment orprevention of allergic rhinitis, allergic conjunctivitis, eosinophilicgranuloma, osteoporosis, arterial restenosis, atherosclerosis,reperfusion injury of the myocardium chronic glomerulonephritis, vernalconjunctivitis, cachexia, transplant rejection, or graft versus hostdisease, comprising the step of administering a therapeuticallyeffective amount, or a prophylactically effective amount, of thecompound according to claim 1 or a pharmaceutically acceptable saltthereof.
 27. A method of treatment or prevention of depression, memoryimpairment, monopolar depression, Parkinson disease, Alzheimer'sdisease, acute and chronic multiple sclerosis, psoriasis, benign ormalignant proliferative skin diseases, atopic dermatitis, urticaria,cancer, tumour growth or cancerous invasion of normal tissues,comprising the step of administering a therapeutically effective amount,or a prophylactically effective amount, of the compound according toclaim 1 or a pharmaceutically acceptable salt thereof.
 28. A method ofenhancing cognition in a healthy subject comprising administering a safecognition enhancing amount of compound of claim
 1. 29. A method ofenhancing cognition in a healthy subject comprising administering asafe, non-emetic, cognition enhancing amount of compound of claim.
 30. Amethod of enhancing cognition in a healthy subject according to claim28, wherein the healthy subject is a human 40 years of age or older. 31.A method of enhancing cognition in a healthy subject according to claim28, wherein the healthy subject is a human 55 years of age or older.32-35. (canceled)